/ en /news/largest-ever-genetic-study-epilepsy-finds-possible-therapeutic-targets <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Ari Navetta</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" class="datetime">October 3, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists have uncovered new genetic links to different types of epilepsy, which could lead to more tailored treatments.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Ari Navetta </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" title="Thursday, October 3, 2024 - 05:03" class="datetime">October 3, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=8nC8epo_ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=aewEWh8X 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=YEIY4d3N 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source 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text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/benjamin-neale">Benjamin Neale</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=QHZF9M1D 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV" width="220" height="186" alt="Lauren Solomon" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">DNA sequencing study suggests common genetic basis for epilepsy</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>The largest and most diverse study to date of epilepsy’s genetic factors has revealed new potential targets for treatment, both shared by and unique to different subtypes of epilepsy. The findings point to factors involved in how neurons communicate and fire, suggesting potential targets for new therapies. In the future, the results could also help doctors tailor treatments to a patient’s genome.</p> <p>Epilepsy is one of the most common neurological disorders. Scientists have long known that genetics play a major role in epilepsy risk, but identifying all of the specific genetic contributions has been challenging, and previous studies have focused on just one or a few genes at a time. Epilepsy also has several subtypes, and while one group called developmental encephalopathies have been connected to several genes, other forms of the disease are less well understood.</p> <p>The study, published in <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank"><em>Nature Neuroscience</em></a>, comes from the <a href="https://epi-25.org/" target="_blank">Epi25 Collaborative</a>, a group of over 200 researchers around the world working to uncover the genetic basis of epilepsy. It builds on previous work by the group using ever-larger cohorts of participants, now up to more than 54,000 people — nearly double previous studies. The researchers — led by <a href="/bios/benjamin-neale">Benjamin Neale</a>, co-director of the <a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a> at the ӳ����ý of MIT and Harvard and a core faculty member of the Analytic and Translational Genetics Unit at Massachusetts General Hospital, and Samuel Berkovic, a professor of medicine at the University of Melbourne —&nbsp;used an approach called whole exome sequencing to look at every gene in the protein-coding region of the genome.</p> <p>“For a complex and heterogeneous disorder like epilepsy, we really wanted to survey as comprehensive a sample as possible across a wide range of genetic variation,” said first author Siwei Chen, a postdoctoral scholar in Neale’s lab.&nbsp;</p> <h2>Ultra-rare variants</h2> <p>Since 2014, Epi25 has collected information from patients with multiple types of epilepsy, including a severe group of epilepsies known as developmental and epileptic encephalopathies &nbsp;as well as more common and milder forms called genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). To find genes that strongly contribute to these subtypes, the authors searched the participants’ exomes for “ultra-rare” variants, or URVs — mutations found less than once per 10,000 participants. If these variants are found more often in people with epilepsy than in those without, or in one type of epilepsy than another, they are more likely to play a role in disease.</p> <p>Since URVs are so rare, and because the scientists wanted to understand many different types of epilepsy, the researchers analyzed DNA from people across the world with a range of different genetic ancestries to find meaningful signals. The study’s 54,000 participants included about 21,000 patients with epilepsy and 33,000 controls.</p> <p>The exomes revealed connections between disease risk and several genes involved in the transmission of signals across the synapses between neurons. In particular, genes coding for ion channel protein complexes, such as receptors for the neurotransmitter GABA_A, play a major role in epilepsy risk across subtypes. While this trend was present for all subtypes, the specific variants contributing to mutations in ion channel proteins varied when looking at each subtype individually.</p> <p>To improve their ability to focus on specific cellular pathways, the researchers aggregated data from genes with similar functions or that encode parts of the same protein complex. For example, data from patients with NAFE showed a strong signal for the gene <em>DEPDC5</em>, which encodes a part of a protein complex called GATOR1 that is critical to brain cell function. When combining it in their analysis with the two genes that encode the rest of the GATOR1 complex, the signal became even stronger, indicating that GATOR1 may be highly involved in a mechanism that contributes to NAFE.</p> <p>In the future, the results could help doctors tailor treatment strategies based on a patient’s genotype, or stratify patients based on the biological effects of specific variants. The researchers say the findings could also improve genetic testing for epilepsy and provide a clearer sense of how genetic variation leads to disease.</p> <p>"These genetic insights provide data-driven starting points for unraveling the biology of the epilepsies," said Neale, "which in turn should help spur future, subtype-tailored advances in diagnosis and treatment."</p> <p>Summary-level data from the study are available via <a href="https://epi25.broadinstitute.org/" target="_blank">the Epi25 WES Browser</a>, an interactive browser hosted by the ӳ����ý, allowing clinicians to easily look up variants seen in their patients and facilitating clinical and translational efforts in follow-up studies.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Epi25 Collaborative. <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank">Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes</a>. <em>Nature Neuroscience</em>. Online October 3, 2024. DOI 10.1038/s41593-024-01747-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/whole-exome-sequencing" hreflang="en">Whole Exome Sequencing</a></div> <div class="field__item"><a href="/broad-tags/ben-neale" hreflang="en">Ben Neale</a></div> </div> </div> </div> </div> </div> Thu, 03 Oct 2024 09:03:18 +0000 arinavetta 5557166 at /news/immune-factor-brain-plays-critical-roles-neuron-function-and-aging <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Ari Navetta</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" class="datetime">October 3, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists have uncovered new genetic links to different types of epilepsy, which could lead to more tailored treatments.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Ari Navetta </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" title="Thursday, October 3, 2024 - 05:03" class="datetime">October 3, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=8nC8epo_ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=aewEWh8X 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=YEIY4d3N 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" src="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY" width="499" height="294" alt="Graphic of EEG readout against blue background with DNA base letters" title="Graphic of EEG readout against blue background with DNA base letters" typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Ricardo Job-Reese, ӳ����ý Communications </div> <div class="media-caption__description"> </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" 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text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/benjamin-neale">Benjamin Neale</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=QHZF9M1D 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV" width="220" height="186" alt="Lauren Solomon" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">DNA sequencing study suggests common genetic basis for epilepsy</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>The largest and most diverse study to date of epilepsy’s genetic factors has revealed new potential targets for treatment, both shared by and unique to different subtypes of epilepsy. The findings point to factors involved in how neurons communicate and fire, suggesting potential targets for new therapies. In the future, the results could also help doctors tailor treatments to a patient’s genome.</p> <p>Epilepsy is one of the most common neurological disorders. Scientists have long known that genetics play a major role in epilepsy risk, but identifying all of the specific genetic contributions has been challenging, and previous studies have focused on just one or a few genes at a time. Epilepsy also has several subtypes, and while one group called developmental encephalopathies have been connected to several genes, other forms of the disease are less well understood.</p> <p>The study, published in <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank"><em>Nature Neuroscience</em></a>, comes from the <a href="https://epi-25.org/" target="_blank">Epi25 Collaborative</a>, a group of over 200 researchers around the world working to uncover the genetic basis of epilepsy. It builds on previous work by the group using ever-larger cohorts of participants, now up to more than 54,000 people — nearly double previous studies. The researchers — led by <a href="/bios/benjamin-neale">Benjamin Neale</a>, co-director of the <a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a> at the ӳ����ý of MIT and Harvard and a core faculty member of the Analytic and Translational Genetics Unit at Massachusetts General Hospital, and Samuel Berkovic, a professor of medicine at the University of Melbourne —&nbsp;used an approach called whole exome sequencing to look at every gene in the protein-coding region of the genome.</p> <p>“For a complex and heterogeneous disorder like epilepsy, we really wanted to survey as comprehensive a sample as possible across a wide range of genetic variation,” said first author Siwei Chen, a postdoctoral scholar in Neale’s lab.&nbsp;</p> <h2>Ultra-rare variants</h2> <p>Since 2014, Epi25 has collected information from patients with multiple types of epilepsy, including a severe group of epilepsies known as developmental and epileptic encephalopathies &nbsp;as well as more common and milder forms called genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). To find genes that strongly contribute to these subtypes, the authors searched the participants’ exomes for “ultra-rare” variants, or URVs — mutations found less than once per 10,000 participants. If these variants are found more often in people with epilepsy than in those without, or in one type of epilepsy than another, they are more likely to play a role in disease.</p> <p>Since URVs are so rare, and because the scientists wanted to understand many different types of epilepsy, the researchers analyzed DNA from people across the world with a range of different genetic ancestries to find meaningful signals. The study’s 54,000 participants included about 21,000 patients with epilepsy and 33,000 controls.</p> <p>The exomes revealed connections between disease risk and several genes involved in the transmission of signals across the synapses between neurons. In particular, genes coding for ion channel protein complexes, such as receptors for the neurotransmitter GABA_A, play a major role in epilepsy risk across subtypes. While this trend was present for all subtypes, the specific variants contributing to mutations in ion channel proteins varied when looking at each subtype individually.</p> <p>To improve their ability to focus on specific cellular pathways, the researchers aggregated data from genes with similar functions or that encode parts of the same protein complex. For example, data from patients with NAFE showed a strong signal for the gene <em>DEPDC5</em>, which encodes a part of a protein complex called GATOR1 that is critical to brain cell function. When combining it in their analysis with the two genes that encode the rest of the GATOR1 complex, the signal became even stronger, indicating that GATOR1 may be highly involved in a mechanism that contributes to NAFE.</p> <p>In the future, the results could help doctors tailor treatment strategies based on a patient’s genotype, or stratify patients based on the biological effects of specific variants. The researchers say the findings could also improve genetic testing for epilepsy and provide a clearer sense of how genetic variation leads to disease.</p> <p>"These genetic insights provide data-driven starting points for unraveling the biology of the epilepsies," said Neale, "which in turn should help spur future, subtype-tailored advances in diagnosis and treatment."</p> <p>Summary-level data from the study are available via <a href="https://epi25.broadinstitute.org/" target="_blank">the Epi25 WES Browser</a>, an interactive browser hosted by the ӳ����ý, allowing clinicians to easily look up variants seen in their patients and facilitating clinical and translational efforts in follow-up studies.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Epi25 Collaborative. <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank">Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes</a>. <em>Nature Neuroscience</em>. Online October 3, 2024. DOI 10.1038/s41593-024-01747-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/whole-exome-sequencing" hreflang="en">Whole Exome Sequencing</a></div> <div class="field__item"><a href="/broad-tags/ben-neale" hreflang="en">Ben Neale</a></div> </div> </div> </div> </div> </div> Fri, 19 Jul 2024 13:42:09 +0000 tulrich@broadinstitute.org 5557141 at /news/brain-chimeroids-offer-window-relationships-between-genetics-and-exposures <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Ari Navetta</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" class="datetime">October 3, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists have uncovered new genetic links to different types of epilepsy, which could lead to more tailored treatments.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Ari Navetta </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" title="Thursday, October 3, 2024 - 05:03" class="datetime">October 3, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=8nC8epo_ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=aewEWh8X 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=YEIY4d3N 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" src="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY" width="499" height="294" alt="Graphic of EEG readout against blue background with DNA base letters" title="Graphic of EEG readout against blue background with DNA base letters" typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Ricardo Job-Reese, ӳ����ý Communications </div> <div class="media-caption__description"> </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" 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</a> <a href="mailto:?subject=&amp;body=/taxonomy/term/613/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons__button share-email" target="_blank" rel="noopener"> <svg width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/benjamin-neale">Benjamin Neale</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=QHZF9M1D 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV" width="220" height="186" alt="Lauren Solomon" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">DNA sequencing study suggests common genetic basis for epilepsy</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>The largest and most diverse study to date of epilepsy’s genetic factors has revealed new potential targets for treatment, both shared by and unique to different subtypes of epilepsy. The findings point to factors involved in how neurons communicate and fire, suggesting potential targets for new therapies. In the future, the results could also help doctors tailor treatments to a patient’s genome.</p> <p>Epilepsy is one of the most common neurological disorders. Scientists have long known that genetics play a major role in epilepsy risk, but identifying all of the specific genetic contributions has been challenging, and previous studies have focused on just one or a few genes at a time. Epilepsy also has several subtypes, and while one group called developmental encephalopathies have been connected to several genes, other forms of the disease are less well understood.</p> <p>The study, published in <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank"><em>Nature Neuroscience</em></a>, comes from the <a href="https://epi-25.org/" target="_blank">Epi25 Collaborative</a>, a group of over 200 researchers around the world working to uncover the genetic basis of epilepsy. It builds on previous work by the group using ever-larger cohorts of participants, now up to more than 54,000 people — nearly double previous studies. The researchers — led by <a href="/bios/benjamin-neale">Benjamin Neale</a>, co-director of the <a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a> at the ӳ����ý of MIT and Harvard and a core faculty member of the Analytic and Translational Genetics Unit at Massachusetts General Hospital, and Samuel Berkovic, a professor of medicine at the University of Melbourne —&nbsp;used an approach called whole exome sequencing to look at every gene in the protein-coding region of the genome.</p> <p>“For a complex and heterogeneous disorder like epilepsy, we really wanted to survey as comprehensive a sample as possible across a wide range of genetic variation,” said first author Siwei Chen, a postdoctoral scholar in Neale’s lab.&nbsp;</p> <h2>Ultra-rare variants</h2> <p>Since 2014, Epi25 has collected information from patients with multiple types of epilepsy, including a severe group of epilepsies known as developmental and epileptic encephalopathies &nbsp;as well as more common and milder forms called genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). To find genes that strongly contribute to these subtypes, the authors searched the participants’ exomes for “ultra-rare” variants, or URVs — mutations found less than once per 10,000 participants. If these variants are found more often in people with epilepsy than in those without, or in one type of epilepsy than another, they are more likely to play a role in disease.</p> <p>Since URVs are so rare, and because the scientists wanted to understand many different types of epilepsy, the researchers analyzed DNA from people across the world with a range of different genetic ancestries to find meaningful signals. The study’s 54,000 participants included about 21,000 patients with epilepsy and 33,000 controls.</p> <p>The exomes revealed connections between disease risk and several genes involved in the transmission of signals across the synapses between neurons. In particular, genes coding for ion channel protein complexes, such as receptors for the neurotransmitter GABA_A, play a major role in epilepsy risk across subtypes. While this trend was present for all subtypes, the specific variants contributing to mutations in ion channel proteins varied when looking at each subtype individually.</p> <p>To improve their ability to focus on specific cellular pathways, the researchers aggregated data from genes with similar functions or that encode parts of the same protein complex. For example, data from patients with NAFE showed a strong signal for the gene <em>DEPDC5</em>, which encodes a part of a protein complex called GATOR1 that is critical to brain cell function. When combining it in their analysis with the two genes that encode the rest of the GATOR1 complex, the signal became even stronger, indicating that GATOR1 may be highly involved in a mechanism that contributes to NAFE.</p> <p>In the future, the results could help doctors tailor treatment strategies based on a patient’s genotype, or stratify patients based on the biological effects of specific variants. The researchers say the findings could also improve genetic testing for epilepsy and provide a clearer sense of how genetic variation leads to disease.</p> <p>"These genetic insights provide data-driven starting points for unraveling the biology of the epilepsies," said Neale, "which in turn should help spur future, subtype-tailored advances in diagnosis and treatment."</p> <p>Summary-level data from the study are available via <a href="https://epi25.broadinstitute.org/" target="_blank">the Epi25 WES Browser</a>, an interactive browser hosted by the ӳ����ý, allowing clinicians to easily look up variants seen in their patients and facilitating clinical and translational efforts in follow-up studies.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Epi25 Collaborative. <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank">Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes</a>. <em>Nature Neuroscience</em>. Online October 3, 2024. DOI 10.1038/s41593-024-01747-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/whole-exome-sequencing" hreflang="en">Whole Exome Sequencing</a></div> <div class="field__item"><a href="/broad-tags/ben-neale" hreflang="en">Ben Neale</a></div> </div> </div> </div> </div> </div> Mon, 08 Jul 2024 14:30:38 +0000 tulrich@broadinstitute.org 5557106 at /news/scientists-uncover-95-regions-genome-linked-ptsd <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Ari Navetta</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" class="datetime">October 3, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists have uncovered new genetic links to different types of epilepsy, which could lead to more tailored treatments.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Ari Navetta </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" title="Thursday, October 3, 2024 - 05:03" class="datetime">October 3, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=8nC8epo_ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=aewEWh8X 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=YEIY4d3N 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" src="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY" width="499" height="294" alt="Graphic of EEG readout against blue background with DNA base letters" title="Graphic of EEG readout against blue background with DNA base letters" typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Ricardo Job-Reese, ӳ����ý Communications </div> <div class="media-caption__description"> </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" 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text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/benjamin-neale">Benjamin Neale</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=QHZF9M1D 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV" width="220" height="186" alt="Lauren Solomon" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">DNA sequencing study suggests common genetic basis for epilepsy</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>The largest and most diverse study to date of epilepsy’s genetic factors has revealed new potential targets for treatment, both shared by and unique to different subtypes of epilepsy. The findings point to factors involved in how neurons communicate and fire, suggesting potential targets for new therapies. In the future, the results could also help doctors tailor treatments to a patient’s genome.</p> <p>Epilepsy is one of the most common neurological disorders. Scientists have long known that genetics play a major role in epilepsy risk, but identifying all of the specific genetic contributions has been challenging, and previous studies have focused on just one or a few genes at a time. Epilepsy also has several subtypes, and while one group called developmental encephalopathies have been connected to several genes, other forms of the disease are less well understood.</p> <p>The study, published in <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank"><em>Nature Neuroscience</em></a>, comes from the <a href="https://epi-25.org/" target="_blank">Epi25 Collaborative</a>, a group of over 200 researchers around the world working to uncover the genetic basis of epilepsy. It builds on previous work by the group using ever-larger cohorts of participants, now up to more than 54,000 people — nearly double previous studies. The researchers — led by <a href="/bios/benjamin-neale">Benjamin Neale</a>, co-director of the <a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a> at the ӳ����ý of MIT and Harvard and a core faculty member of the Analytic and Translational Genetics Unit at Massachusetts General Hospital, and Samuel Berkovic, a professor of medicine at the University of Melbourne —&nbsp;used an approach called whole exome sequencing to look at every gene in the protein-coding region of the genome.</p> <p>“For a complex and heterogeneous disorder like epilepsy, we really wanted to survey as comprehensive a sample as possible across a wide range of genetic variation,” said first author Siwei Chen, a postdoctoral scholar in Neale’s lab.&nbsp;</p> <h2>Ultra-rare variants</h2> <p>Since 2014, Epi25 has collected information from patients with multiple types of epilepsy, including a severe group of epilepsies known as developmental and epileptic encephalopathies &nbsp;as well as more common and milder forms called genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). To find genes that strongly contribute to these subtypes, the authors searched the participants’ exomes for “ultra-rare” variants, or URVs — mutations found less than once per 10,000 participants. If these variants are found more often in people with epilepsy than in those without, or in one type of epilepsy than another, they are more likely to play a role in disease.</p> <p>Since URVs are so rare, and because the scientists wanted to understand many different types of epilepsy, the researchers analyzed DNA from people across the world with a range of different genetic ancestries to find meaningful signals. The study’s 54,000 participants included about 21,000 patients with epilepsy and 33,000 controls.</p> <p>The exomes revealed connections between disease risk and several genes involved in the transmission of signals across the synapses between neurons. In particular, genes coding for ion channel protein complexes, such as receptors for the neurotransmitter GABA_A, play a major role in epilepsy risk across subtypes. While this trend was present for all subtypes, the specific variants contributing to mutations in ion channel proteins varied when looking at each subtype individually.</p> <p>To improve their ability to focus on specific cellular pathways, the researchers aggregated data from genes with similar functions or that encode parts of the same protein complex. For example, data from patients with NAFE showed a strong signal for the gene <em>DEPDC5</em>, which encodes a part of a protein complex called GATOR1 that is critical to brain cell function. When combining it in their analysis with the two genes that encode the rest of the GATOR1 complex, the signal became even stronger, indicating that GATOR1 may be highly involved in a mechanism that contributes to NAFE.</p> <p>In the future, the results could help doctors tailor treatment strategies based on a patient’s genotype, or stratify patients based on the biological effects of specific variants. The researchers say the findings could also improve genetic testing for epilepsy and provide a clearer sense of how genetic variation leads to disease.</p> <p>"These genetic insights provide data-driven starting points for unraveling the biology of the epilepsies," said Neale, "which in turn should help spur future, subtype-tailored advances in diagnosis and treatment."</p> <p>Summary-level data from the study are available via <a href="https://epi25.broadinstitute.org/" target="_blank">the Epi25 WES Browser</a>, an interactive browser hosted by the ӳ����ý, allowing clinicians to easily look up variants seen in their patients and facilitating clinical and translational efforts in follow-up studies.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Epi25 Collaborative. <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank">Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes</a>. <em>Nature Neuroscience</em>. Online October 3, 2024. DOI 10.1038/s41593-024-01747-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/whole-exome-sequencing" hreflang="en">Whole Exome Sequencing</a></div> <div class="field__item"><a href="/broad-tags/ben-neale" hreflang="en">Ben Neale</a></div> </div> </div> </div> </div> </div> Thu, 18 Apr 2024 09:00:00 +0000 adicorat 5556766 at /news/schizophrenia-and-aging-may-share-common-biological-basis <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Ari Navetta</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" class="datetime">October 3, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists have uncovered new genetic links to different types of epilepsy, which could lead to more tailored treatments.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Ari Navetta </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" title="Thursday, October 3, 2024 - 05:03" class="datetime">October 3, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=8nC8epo_ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=aewEWh8X 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=YEIY4d3N 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" src="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY" width="499" height="294" alt="Graphic of EEG readout against blue background with DNA base letters" title="Graphic of EEG readout against blue background with DNA base letters" typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Ricardo Job-Reese, ӳ����ý Communications </div> <div class="media-caption__description"> </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" 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text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/benjamin-neale">Benjamin Neale</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=QHZF9M1D 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV" width="220" height="186" alt="Lauren Solomon" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">DNA sequencing study suggests common genetic basis for epilepsy</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>The largest and most diverse study to date of epilepsy’s genetic factors has revealed new potential targets for treatment, both shared by and unique to different subtypes of epilepsy. The findings point to factors involved in how neurons communicate and fire, suggesting potential targets for new therapies. In the future, the results could also help doctors tailor treatments to a patient’s genome.</p> <p>Epilepsy is one of the most common neurological disorders. Scientists have long known that genetics play a major role in epilepsy risk, but identifying all of the specific genetic contributions has been challenging, and previous studies have focused on just one or a few genes at a time. Epilepsy also has several subtypes, and while one group called developmental encephalopathies have been connected to several genes, other forms of the disease are less well understood.</p> <p>The study, published in <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank"><em>Nature Neuroscience</em></a>, comes from the <a href="https://epi-25.org/" target="_blank">Epi25 Collaborative</a>, a group of over 200 researchers around the world working to uncover the genetic basis of epilepsy. It builds on previous work by the group using ever-larger cohorts of participants, now up to more than 54,000 people — nearly double previous studies. The researchers — led by <a href="/bios/benjamin-neale">Benjamin Neale</a>, co-director of the <a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a> at the ӳ����ý of MIT and Harvard and a core faculty member of the Analytic and Translational Genetics Unit at Massachusetts General Hospital, and Samuel Berkovic, a professor of medicine at the University of Melbourne —&nbsp;used an approach called whole exome sequencing to look at every gene in the protein-coding region of the genome.</p> <p>“For a complex and heterogeneous disorder like epilepsy, we really wanted to survey as comprehensive a sample as possible across a wide range of genetic variation,” said first author Siwei Chen, a postdoctoral scholar in Neale’s lab.&nbsp;</p> <h2>Ultra-rare variants</h2> <p>Since 2014, Epi25 has collected information from patients with multiple types of epilepsy, including a severe group of epilepsies known as developmental and epileptic encephalopathies &nbsp;as well as more common and milder forms called genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). To find genes that strongly contribute to these subtypes, the authors searched the participants’ exomes for “ultra-rare” variants, or URVs — mutations found less than once per 10,000 participants. If these variants are found more often in people with epilepsy than in those without, or in one type of epilepsy than another, they are more likely to play a role in disease.</p> <p>Since URVs are so rare, and because the scientists wanted to understand many different types of epilepsy, the researchers analyzed DNA from people across the world with a range of different genetic ancestries to find meaningful signals. The study’s 54,000 participants included about 21,000 patients with epilepsy and 33,000 controls.</p> <p>The exomes revealed connections between disease risk and several genes involved in the transmission of signals across the synapses between neurons. In particular, genes coding for ion channel protein complexes, such as receptors for the neurotransmitter GABA_A, play a major role in epilepsy risk across subtypes. While this trend was present for all subtypes, the specific variants contributing to mutations in ion channel proteins varied when looking at each subtype individually.</p> <p>To improve their ability to focus on specific cellular pathways, the researchers aggregated data from genes with similar functions or that encode parts of the same protein complex. For example, data from patients with NAFE showed a strong signal for the gene <em>DEPDC5</em>, which encodes a part of a protein complex called GATOR1 that is critical to brain cell function. When combining it in their analysis with the two genes that encode the rest of the GATOR1 complex, the signal became even stronger, indicating that GATOR1 may be highly involved in a mechanism that contributes to NAFE.</p> <p>In the future, the results could help doctors tailor treatment strategies based on a patient’s genotype, or stratify patients based on the biological effects of specific variants. The researchers say the findings could also improve genetic testing for epilepsy and provide a clearer sense of how genetic variation leads to disease.</p> <p>"These genetic insights provide data-driven starting points for unraveling the biology of the epilepsies," said Neale, "which in turn should help spur future, subtype-tailored advances in diagnosis and treatment."</p> <p>Summary-level data from the study are available via <a href="https://epi25.broadinstitute.org/" target="_blank">the Epi25 WES Browser</a>, an interactive browser hosted by the ӳ����ý, allowing clinicians to easily look up variants seen in their patients and facilitating clinical and translational efforts in follow-up studies.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Epi25 Collaborative. <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank">Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes</a>. <em>Nature Neuroscience</em>. Online October 3, 2024. DOI 10.1038/s41593-024-01747-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/whole-exome-sequencing" hreflang="en">Whole Exome Sequencing</a></div> <div class="field__item"><a href="/broad-tags/ben-neale" hreflang="en">Ben Neale</a></div> </div> </div> </div> </div> </div> Wed, 06 Mar 2024 16:00:00 +0000 adicorat 5556511 at /news/whyiscience-qa-software-engineer-develops-computational-tools-psychiatric-and-brain-research <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Ari Navetta</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" class="datetime">October 3, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists have uncovered new genetic links to different types of epilepsy, which could lead to more tailored treatments.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Ari Navetta </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" title="Thursday, October 3, 2024 - 05:03" class="datetime">October 3, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=8nC8epo_ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=aewEWh8X 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=YEIY4d3N 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" src="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY" width="499" height="294" alt="Graphic of EEG readout against blue background with DNA base letters" title="Graphic of EEG readout against blue background with DNA base letters" typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Ricardo Job-Reese, ӳ����ý Communications </div> <div class="media-caption__description"> </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" 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class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=QHZF9M1D 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV" width="220" height="186" alt="Lauren Solomon" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">DNA sequencing study suggests common genetic basis for epilepsy</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>The largest and most diverse study to date of epilepsy’s genetic factors has revealed new potential targets for treatment, both shared by and unique to different subtypes of epilepsy. The findings point to factors involved in how neurons communicate and fire, suggesting potential targets for new therapies. In the future, the results could also help doctors tailor treatments to a patient’s genome.</p> <p>Epilepsy is one of the most common neurological disorders. Scientists have long known that genetics play a major role in epilepsy risk, but identifying all of the specific genetic contributions has been challenging, and previous studies have focused on just one or a few genes at a time. Epilepsy also has several subtypes, and while one group called developmental encephalopathies have been connected to several genes, other forms of the disease are less well understood.</p> <p>The study, published in <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank"><em>Nature Neuroscience</em></a>, comes from the <a href="https://epi-25.org/" target="_blank">Epi25 Collaborative</a>, a group of over 200 researchers around the world working to uncover the genetic basis of epilepsy. It builds on previous work by the group using ever-larger cohorts of participants, now up to more than 54,000 people — nearly double previous studies. The researchers — led by <a href="/bios/benjamin-neale">Benjamin Neale</a>, co-director of the <a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a> at the ӳ����ý of MIT and Harvard and a core faculty member of the Analytic and Translational Genetics Unit at Massachusetts General Hospital, and Samuel Berkovic, a professor of medicine at the University of Melbourne —&nbsp;used an approach called whole exome sequencing to look at every gene in the protein-coding region of the genome.</p> <p>“For a complex and heterogeneous disorder like epilepsy, we really wanted to survey as comprehensive a sample as possible across a wide range of genetic variation,” said first author Siwei Chen, a postdoctoral scholar in Neale’s lab.&nbsp;</p> <h2>Ultra-rare variants</h2> <p>Since 2014, Epi25 has collected information from patients with multiple types of epilepsy, including a severe group of epilepsies known as developmental and epileptic encephalopathies &nbsp;as well as more common and milder forms called genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). To find genes that strongly contribute to these subtypes, the authors searched the participants’ exomes for “ultra-rare” variants, or URVs — mutations found less than once per 10,000 participants. If these variants are found more often in people with epilepsy than in those without, or in one type of epilepsy than another, they are more likely to play a role in disease.</p> <p>Since URVs are so rare, and because the scientists wanted to understand many different types of epilepsy, the researchers analyzed DNA from people across the world with a range of different genetic ancestries to find meaningful signals. The study’s 54,000 participants included about 21,000 patients with epilepsy and 33,000 controls.</p> <p>The exomes revealed connections between disease risk and several genes involved in the transmission of signals across the synapses between neurons. In particular, genes coding for ion channel protein complexes, such as receptors for the neurotransmitter GABA_A, play a major role in epilepsy risk across subtypes. While this trend was present for all subtypes, the specific variants contributing to mutations in ion channel proteins varied when looking at each subtype individually.</p> <p>To improve their ability to focus on specific cellular pathways, the researchers aggregated data from genes with similar functions or that encode parts of the same protein complex. For example, data from patients with NAFE showed a strong signal for the gene <em>DEPDC5</em>, which encodes a part of a protein complex called GATOR1 that is critical to brain cell function. When combining it in their analysis with the two genes that encode the rest of the GATOR1 complex, the signal became even stronger, indicating that GATOR1 may be highly involved in a mechanism that contributes to NAFE.</p> <p>In the future, the results could help doctors tailor treatment strategies based on a patient’s genotype, or stratify patients based on the biological effects of specific variants. The researchers say the findings could also improve genetic testing for epilepsy and provide a clearer sense of how genetic variation leads to disease.</p> <p>"These genetic insights provide data-driven starting points for unraveling the biology of the epilepsies," said Neale, "which in turn should help spur future, subtype-tailored advances in diagnosis and treatment."</p> <p>Summary-level data from the study are available via <a href="https://epi25.broadinstitute.org/" target="_blank">the Epi25 WES Browser</a>, an interactive browser hosted by the ӳ����ý, allowing clinicians to easily look up variants seen in their patients and facilitating clinical and translational efforts in follow-up studies.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Epi25 Collaborative. <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank">Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes</a>. <em>Nature Neuroscience</em>. Online October 3, 2024. DOI 10.1038/s41593-024-01747-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/whole-exome-sequencing" hreflang="en">Whole Exome Sequencing</a></div> <div class="field__item"><a href="/broad-tags/ben-neale" hreflang="en">Ben Neale</a></div> </div> </div> </div> </div> </div> Wed, 21 Feb 2024 15:00:00 +0000 chenders@broadinstitute.org 5556501 at /news/qa-how-jump-start-new-psychiatric-and-neurological-drug-development <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Ari Navetta</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" class="datetime">October 3, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists have uncovered new genetic links to different types of epilepsy, which could lead to more tailored treatments.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Ari Navetta </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" title="Thursday, October 3, 2024 - 05:03" class="datetime">October 3, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=8nC8epo_ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=aewEWh8X 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=YEIY4d3N 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" src="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY" width="499" height="294" alt="Graphic of EEG readout against blue background with DNA base letters" title="Graphic of EEG readout against blue background with DNA base letters" typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Ricardo Job-Reese, ӳ����ý Communications </div> <div class="media-caption__description"> </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" 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text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/benjamin-neale">Benjamin Neale</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=QHZF9M1D 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV" width="220" height="186" alt="Lauren Solomon" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">DNA sequencing study suggests common genetic basis for epilepsy</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>The largest and most diverse study to date of epilepsy’s genetic factors has revealed new potential targets for treatment, both shared by and unique to different subtypes of epilepsy. The findings point to factors involved in how neurons communicate and fire, suggesting potential targets for new therapies. In the future, the results could also help doctors tailor treatments to a patient’s genome.</p> <p>Epilepsy is one of the most common neurological disorders. Scientists have long known that genetics play a major role in epilepsy risk, but identifying all of the specific genetic contributions has been challenging, and previous studies have focused on just one or a few genes at a time. Epilepsy also has several subtypes, and while one group called developmental encephalopathies have been connected to several genes, other forms of the disease are less well understood.</p> <p>The study, published in <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank"><em>Nature Neuroscience</em></a>, comes from the <a href="https://epi-25.org/" target="_blank">Epi25 Collaborative</a>, a group of over 200 researchers around the world working to uncover the genetic basis of epilepsy. It builds on previous work by the group using ever-larger cohorts of participants, now up to more than 54,000 people — nearly double previous studies. The researchers — led by <a href="/bios/benjamin-neale">Benjamin Neale</a>, co-director of the <a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a> at the ӳ����ý of MIT and Harvard and a core faculty member of the Analytic and Translational Genetics Unit at Massachusetts General Hospital, and Samuel Berkovic, a professor of medicine at the University of Melbourne —&nbsp;used an approach called whole exome sequencing to look at every gene in the protein-coding region of the genome.</p> <p>“For a complex and heterogeneous disorder like epilepsy, we really wanted to survey as comprehensive a sample as possible across a wide range of genetic variation,” said first author Siwei Chen, a postdoctoral scholar in Neale’s lab.&nbsp;</p> <h2>Ultra-rare variants</h2> <p>Since 2014, Epi25 has collected information from patients with multiple types of epilepsy, including a severe group of epilepsies known as developmental and epileptic encephalopathies &nbsp;as well as more common and milder forms called genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). To find genes that strongly contribute to these subtypes, the authors searched the participants’ exomes for “ultra-rare” variants, or URVs — mutations found less than once per 10,000 participants. If these variants are found more often in people with epilepsy than in those without, or in one type of epilepsy than another, they are more likely to play a role in disease.</p> <p>Since URVs are so rare, and because the scientists wanted to understand many different types of epilepsy, the researchers analyzed DNA from people across the world with a range of different genetic ancestries to find meaningful signals. The study’s 54,000 participants included about 21,000 patients with epilepsy and 33,000 controls.</p> <p>The exomes revealed connections between disease risk and several genes involved in the transmission of signals across the synapses between neurons. In particular, genes coding for ion channel protein complexes, such as receptors for the neurotransmitter GABA_A, play a major role in epilepsy risk across subtypes. While this trend was present for all subtypes, the specific variants contributing to mutations in ion channel proteins varied when looking at each subtype individually.</p> <p>To improve their ability to focus on specific cellular pathways, the researchers aggregated data from genes with similar functions or that encode parts of the same protein complex. For example, data from patients with NAFE showed a strong signal for the gene <em>DEPDC5</em>, which encodes a part of a protein complex called GATOR1 that is critical to brain cell function. When combining it in their analysis with the two genes that encode the rest of the GATOR1 complex, the signal became even stronger, indicating that GATOR1 may be highly involved in a mechanism that contributes to NAFE.</p> <p>In the future, the results could help doctors tailor treatment strategies based on a patient’s genotype, or stratify patients based on the biological effects of specific variants. The researchers say the findings could also improve genetic testing for epilepsy and provide a clearer sense of how genetic variation leads to disease.</p> <p>"These genetic insights provide data-driven starting points for unraveling the biology of the epilepsies," said Neale, "which in turn should help spur future, subtype-tailored advances in diagnosis and treatment."</p> <p>Summary-level data from the study are available via <a href="https://epi25.broadinstitute.org/" target="_blank">the Epi25 WES Browser</a>, an interactive browser hosted by the ӳ����ý, allowing clinicians to easily look up variants seen in their patients and facilitating clinical and translational efforts in follow-up studies.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Epi25 Collaborative. <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank">Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes</a>. <em>Nature Neuroscience</em>. Online October 3, 2024. DOI 10.1038/s41593-024-01747-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/whole-exome-sequencing" hreflang="en">Whole Exome Sequencing</a></div> <div class="field__item"><a href="/broad-tags/ben-neale" hreflang="en">Ben Neale</a></div> </div> </div> </div> </div> </div> Mon, 18 Dec 2023 15:02:23 +0000 tulrich@broadinstitute.org 5556201 at /news/schizophrenia-gene-mutation-causes-many-changes-mouse-brain <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Ari Navetta</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" class="datetime">October 3, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists have uncovered new genetic links to different types of epilepsy, which could lead to more tailored treatments.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Ari Navetta </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" title="Thursday, October 3, 2024 - 05:03" class="datetime">October 3, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=8nC8epo_ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=aewEWh8X 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=YEIY4d3N 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" src="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY" width="499" height="294" alt="Graphic of EEG readout against blue background with DNA base letters" title="Graphic of EEG readout against blue background with DNA base letters" typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Ricardo Job-Reese, ӳ����ý Communications </div> <div class="media-caption__description"> </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" 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</a> <a href="mailto:?subject=&amp;body=/taxonomy/term/613/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons__button share-email" target="_blank" rel="noopener"> <svg width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/benjamin-neale">Benjamin Neale</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=QHZF9M1D 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV" width="220" height="186" alt="Lauren Solomon" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">DNA sequencing study suggests common genetic basis for epilepsy</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>The largest and most diverse study to date of epilepsy’s genetic factors has revealed new potential targets for treatment, both shared by and unique to different subtypes of epilepsy. The findings point to factors involved in how neurons communicate and fire, suggesting potential targets for new therapies. In the future, the results could also help doctors tailor treatments to a patient’s genome.</p> <p>Epilepsy is one of the most common neurological disorders. Scientists have long known that genetics play a major role in epilepsy risk, but identifying all of the specific genetic contributions has been challenging, and previous studies have focused on just one or a few genes at a time. Epilepsy also has several subtypes, and while one group called developmental encephalopathies have been connected to several genes, other forms of the disease are less well understood.</p> <p>The study, published in <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank"><em>Nature Neuroscience</em></a>, comes from the <a href="https://epi-25.org/" target="_blank">Epi25 Collaborative</a>, a group of over 200 researchers around the world working to uncover the genetic basis of epilepsy. It builds on previous work by the group using ever-larger cohorts of participants, now up to more than 54,000 people — nearly double previous studies. The researchers — led by <a href="/bios/benjamin-neale">Benjamin Neale</a>, co-director of the <a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a> at the ӳ����ý of MIT and Harvard and a core faculty member of the Analytic and Translational Genetics Unit at Massachusetts General Hospital, and Samuel Berkovic, a professor of medicine at the University of Melbourne —&nbsp;used an approach called whole exome sequencing to look at every gene in the protein-coding region of the genome.</p> <p>“For a complex and heterogeneous disorder like epilepsy, we really wanted to survey as comprehensive a sample as possible across a wide range of genetic variation,” said first author Siwei Chen, a postdoctoral scholar in Neale’s lab.&nbsp;</p> <h2>Ultra-rare variants</h2> <p>Since 2014, Epi25 has collected information from patients with multiple types of epilepsy, including a severe group of epilepsies known as developmental and epileptic encephalopathies &nbsp;as well as more common and milder forms called genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). To find genes that strongly contribute to these subtypes, the authors searched the participants’ exomes for “ultra-rare” variants, or URVs — mutations found less than once per 10,000 participants. If these variants are found more often in people with epilepsy than in those without, or in one type of epilepsy than another, they are more likely to play a role in disease.</p> <p>Since URVs are so rare, and because the scientists wanted to understand many different types of epilepsy, the researchers analyzed DNA from people across the world with a range of different genetic ancestries to find meaningful signals. The study’s 54,000 participants included about 21,000 patients with epilepsy and 33,000 controls.</p> <p>The exomes revealed connections between disease risk and several genes involved in the transmission of signals across the synapses between neurons. In particular, genes coding for ion channel protein complexes, such as receptors for the neurotransmitter GABA_A, play a major role in epilepsy risk across subtypes. While this trend was present for all subtypes, the specific variants contributing to mutations in ion channel proteins varied when looking at each subtype individually.</p> <p>To improve their ability to focus on specific cellular pathways, the researchers aggregated data from genes with similar functions or that encode parts of the same protein complex. For example, data from patients with NAFE showed a strong signal for the gene <em>DEPDC5</em>, which encodes a part of a protein complex called GATOR1 that is critical to brain cell function. When combining it in their analysis with the two genes that encode the rest of the GATOR1 complex, the signal became even stronger, indicating that GATOR1 may be highly involved in a mechanism that contributes to NAFE.</p> <p>In the future, the results could help doctors tailor treatment strategies based on a patient’s genotype, or stratify patients based on the biological effects of specific variants. The researchers say the findings could also improve genetic testing for epilepsy and provide a clearer sense of how genetic variation leads to disease.</p> <p>"These genetic insights provide data-driven starting points for unraveling the biology of the epilepsies," said Neale, "which in turn should help spur future, subtype-tailored advances in diagnosis and treatment."</p> <p>Summary-level data from the study are available via <a href="https://epi25.broadinstitute.org/" target="_blank">the Epi25 WES Browser</a>, an interactive browser hosted by the ӳ����ý, allowing clinicians to easily look up variants seen in their patients and facilitating clinical and translational efforts in follow-up studies.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Epi25 Collaborative. <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank">Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes</a>. <em>Nature Neuroscience</em>. Online October 3, 2024. DOI 10.1038/s41593-024-01747-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/whole-exome-sequencing" hreflang="en">Whole Exome Sequencing</a></div> <div class="field__item"><a href="/broad-tags/ben-neale" hreflang="en">Ben Neale</a></div> </div> </div> </div> </div> </div> Thu, 31 Aug 2023 15:00:00 +0000 leah@broadinstitute.org 5555566 at /news/survey-brain-cell-junctions-shows-striking-similarities-between-schizophrenia-and-bipolar <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Ari Navetta</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" class="datetime">October 3, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists have uncovered new genetic links to different types of epilepsy, which could lead to more tailored treatments.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Ari Navetta </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" title="Thursday, October 3, 2024 - 05:03" class="datetime">October 3, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=8nC8epo_ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=aewEWh8X 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=YEIY4d3N 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" src="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY" width="499" height="294" alt="Graphic of EEG readout against blue background with DNA base letters" title="Graphic of EEG readout against blue background with DNA base letters" typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Ricardo Job-Reese, ӳ����ý Communications </div> <div class="media-caption__description"> </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" 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text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/benjamin-neale">Benjamin Neale</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=QHZF9M1D 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV" width="220" height="186" alt="Lauren Solomon" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">DNA sequencing study suggests common genetic basis for epilepsy</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>The largest and most diverse study to date of epilepsy’s genetic factors has revealed new potential targets for treatment, both shared by and unique to different subtypes of epilepsy. The findings point to factors involved in how neurons communicate and fire, suggesting potential targets for new therapies. In the future, the results could also help doctors tailor treatments to a patient’s genome.</p> <p>Epilepsy is one of the most common neurological disorders. Scientists have long known that genetics play a major role in epilepsy risk, but identifying all of the specific genetic contributions has been challenging, and previous studies have focused on just one or a few genes at a time. Epilepsy also has several subtypes, and while one group called developmental encephalopathies have been connected to several genes, other forms of the disease are less well understood.</p> <p>The study, published in <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank"><em>Nature Neuroscience</em></a>, comes from the <a href="https://epi-25.org/" target="_blank">Epi25 Collaborative</a>, a group of over 200 researchers around the world working to uncover the genetic basis of epilepsy. It builds on previous work by the group using ever-larger cohorts of participants, now up to more than 54,000 people — nearly double previous studies. The researchers — led by <a href="/bios/benjamin-neale">Benjamin Neale</a>, co-director of the <a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a> at the ӳ����ý of MIT and Harvard and a core faculty member of the Analytic and Translational Genetics Unit at Massachusetts General Hospital, and Samuel Berkovic, a professor of medicine at the University of Melbourne —&nbsp;used an approach called whole exome sequencing to look at every gene in the protein-coding region of the genome.</p> <p>“For a complex and heterogeneous disorder like epilepsy, we really wanted to survey as comprehensive a sample as possible across a wide range of genetic variation,” said first author Siwei Chen, a postdoctoral scholar in Neale’s lab.&nbsp;</p> <h2>Ultra-rare variants</h2> <p>Since 2014, Epi25 has collected information from patients with multiple types of epilepsy, including a severe group of epilepsies known as developmental and epileptic encephalopathies &nbsp;as well as more common and milder forms called genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). To find genes that strongly contribute to these subtypes, the authors searched the participants’ exomes for “ultra-rare” variants, or URVs — mutations found less than once per 10,000 participants. If these variants are found more often in people with epilepsy than in those without, or in one type of epilepsy than another, they are more likely to play a role in disease.</p> <p>Since URVs are so rare, and because the scientists wanted to understand many different types of epilepsy, the researchers analyzed DNA from people across the world with a range of different genetic ancestries to find meaningful signals. The study’s 54,000 participants included about 21,000 patients with epilepsy and 33,000 controls.</p> <p>The exomes revealed connections between disease risk and several genes involved in the transmission of signals across the synapses between neurons. In particular, genes coding for ion channel protein complexes, such as receptors for the neurotransmitter GABA_A, play a major role in epilepsy risk across subtypes. While this trend was present for all subtypes, the specific variants contributing to mutations in ion channel proteins varied when looking at each subtype individually.</p> <p>To improve their ability to focus on specific cellular pathways, the researchers aggregated data from genes with similar functions or that encode parts of the same protein complex. For example, data from patients with NAFE showed a strong signal for the gene <em>DEPDC5</em>, which encodes a part of a protein complex called GATOR1 that is critical to brain cell function. When combining it in their analysis with the two genes that encode the rest of the GATOR1 complex, the signal became even stronger, indicating that GATOR1 may be highly involved in a mechanism that contributes to NAFE.</p> <p>In the future, the results could help doctors tailor treatment strategies based on a patient’s genotype, or stratify patients based on the biological effects of specific variants. The researchers say the findings could also improve genetic testing for epilepsy and provide a clearer sense of how genetic variation leads to disease.</p> <p>"These genetic insights provide data-driven starting points for unraveling the biology of the epilepsies," said Neale, "which in turn should help spur future, subtype-tailored advances in diagnosis and treatment."</p> <p>Summary-level data from the study are available via <a href="https://epi25.broadinstitute.org/" target="_blank">the Epi25 WES Browser</a>, an interactive browser hosted by the ӳ����ý, allowing clinicians to easily look up variants seen in their patients and facilitating clinical and translational efforts in follow-up studies.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Epi25 Collaborative. <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank">Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes</a>. <em>Nature Neuroscience</em>. Online October 3, 2024. DOI 10.1038/s41593-024-01747-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/whole-exome-sequencing" hreflang="en">Whole Exome Sequencing</a></div> <div class="field__item"><a href="/broad-tags/ben-neale" hreflang="en">Ben Neale</a></div> </div> </div> </div> </div> </div> Thu, 11 May 2023 19:47:44 +0000 leah@broadinstitute.org 1282206 at /news/researchers-map-brain-cell-changes-alzheimers-disease <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Ari Navetta</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" class="datetime">October 3, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Largest-ever genetic study of epilepsy finds possible therapeutic targets</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists have uncovered new genetic links to different types of epilepsy, which could lead to more tailored treatments.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Ari Navetta </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-03T05:03:18-04:00" title="Thursday, October 3, 2024 - 05:03" class="datetime">October 3, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=sppqg5EJ 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=8nC8epo_ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=aewEWh8X 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=YEIY4d3N 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" src="/files/styles/multiple_ct_header_phone/public/longstory/Epi25-NewStory_v02.png?h=ae0fde30&amp;itok=-fDzPmvY" width="499" height="294" alt="Graphic of EEG readout against blue background with DNA base letters" title="Graphic of EEG readout against blue background with DNA base letters" typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Ricardo Job-Reese, ӳ����ý Communications </div> <div class="media-caption__description"> </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" 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text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/benjamin-neale">Benjamin Neale</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=paj8GZuu 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=eqs88NvW 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=QHZF9M1D 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Epilepsy-WES-Feature_main_social-3B.png?h=d3e04ee7&amp;itok=Z1slOPxV" width="220" height="186" alt="Lauren Solomon" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/dna-sequencing-study-suggests-common-genetic-basis-epilepsy-0" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">DNA sequencing study suggests common genetic basis for epilepsy</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>The largest and most diverse study to date of epilepsy’s genetic factors has revealed new potential targets for treatment, both shared by and unique to different subtypes of epilepsy. The findings point to factors involved in how neurons communicate and fire, suggesting potential targets for new therapies. In the future, the results could also help doctors tailor treatments to a patient’s genome.</p> <p>Epilepsy is one of the most common neurological disorders. Scientists have long known that genetics play a major role in epilepsy risk, but identifying all of the specific genetic contributions has been challenging, and previous studies have focused on just one or a few genes at a time. Epilepsy also has several subtypes, and while one group called developmental encephalopathies have been connected to several genes, other forms of the disease are less well understood.</p> <p>The study, published in <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank"><em>Nature Neuroscience</em></a>, comes from the <a href="https://epi-25.org/" target="_blank">Epi25 Collaborative</a>, a group of over 200 researchers around the world working to uncover the genetic basis of epilepsy. It builds on previous work by the group using ever-larger cohorts of participants, now up to more than 54,000 people — nearly double previous studies. The researchers — led by <a href="/bios/benjamin-neale">Benjamin Neale</a>, co-director of the <a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a> at the ӳ����ý of MIT and Harvard and a core faculty member of the Analytic and Translational Genetics Unit at Massachusetts General Hospital, and Samuel Berkovic, a professor of medicine at the University of Melbourne —&nbsp;used an approach called whole exome sequencing to look at every gene in the protein-coding region of the genome.</p> <p>“For a complex and heterogeneous disorder like epilepsy, we really wanted to survey as comprehensive a sample as possible across a wide range of genetic variation,” said first author Siwei Chen, a postdoctoral scholar in Neale’s lab.&nbsp;</p> <h2>Ultra-rare variants</h2> <p>Since 2014, Epi25 has collected information from patients with multiple types of epilepsy, including a severe group of epilepsies known as developmental and epileptic encephalopathies &nbsp;as well as more common and milder forms called genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). To find genes that strongly contribute to these subtypes, the authors searched the participants’ exomes for “ultra-rare” variants, or URVs — mutations found less than once per 10,000 participants. If these variants are found more often in people with epilepsy than in those without, or in one type of epilepsy than another, they are more likely to play a role in disease.</p> <p>Since URVs are so rare, and because the scientists wanted to understand many different types of epilepsy, the researchers analyzed DNA from people across the world with a range of different genetic ancestries to find meaningful signals. The study’s 54,000 participants included about 21,000 patients with epilepsy and 33,000 controls.</p> <p>The exomes revealed connections between disease risk and several genes involved in the transmission of signals across the synapses between neurons. In particular, genes coding for ion channel protein complexes, such as receptors for the neurotransmitter GABA_A, play a major role in epilepsy risk across subtypes. While this trend was present for all subtypes, the specific variants contributing to mutations in ion channel proteins varied when looking at each subtype individually.</p> <p>To improve their ability to focus on specific cellular pathways, the researchers aggregated data from genes with similar functions or that encode parts of the same protein complex. For example, data from patients with NAFE showed a strong signal for the gene <em>DEPDC5</em>, which encodes a part of a protein complex called GATOR1 that is critical to brain cell function. When combining it in their analysis with the two genes that encode the rest of the GATOR1 complex, the signal became even stronger, indicating that GATOR1 may be highly involved in a mechanism that contributes to NAFE.</p> <p>In the future, the results could help doctors tailor treatment strategies based on a patient’s genotype, or stratify patients based on the biological effects of specific variants. The researchers say the findings could also improve genetic testing for epilepsy and provide a clearer sense of how genetic variation leads to disease.</p> <p>"These genetic insights provide data-driven starting points for unraveling the biology of the epilepsies," said Neale, "which in turn should help spur future, subtype-tailored advances in diagnosis and treatment."</p> <p>Summary-level data from the study are available via <a href="https://epi25.broadinstitute.org/" target="_blank">the Epi25 WES Browser</a>, an interactive browser hosted by the ӳ����ý, allowing clinicians to easily look up variants seen in their patients and facilitating clinical and translational efforts in follow-up studies.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Epi25 Collaborative. <a href="https://www.nature.com/articles/s41593-024-01747-8" target="_blank">Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes</a>. <em>Nature Neuroscience</em>. Online October 3, 2024. DOI 10.1038/s41593-024-01747-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/whole-exome-sequencing" hreflang="en">Whole Exome Sequencing</a></div> <div class="field__item"><a href="/broad-tags/ben-neale" hreflang="en">Ben Neale</a></div> </div> </div> </div> </div> </div> Thu, 02 Feb 2023 16:00:00 +0000 adicorat 1281436 at