Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes.
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Abstract | Over 100 associated genetic loci have been robustly associated with schizophrenia. Gene prioritization and pathway analysis have focused on a priori hypotheses and thus may have been unduly influenced by prior assumptions and missed important causal genes and pathways. Using a data-driven approach, we show that genes in associated loci: (1) are highly expressed in cortical brain areas; (2) are enriched for ion channel pathways (false discovery rates 0.05); and (3) contain 62 genes that are functionally related to each other and hence represent promising candidates for experimental follow up. We validate the relevance of the prioritized genes by showing that they are enriched for rare disruptive variants and de novo variants from schizophrenia sequencing studies (odds ratio 1.67, P = 0.039), and are enriched for genes encoding members of mouse and human postsynaptic density proteomes (odds ratio 4.56, P = 5.00 × 10(-4); odds ratio 2.60, P = 0.049).The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Author. |
Year of Publication | 2016
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Journal | Hum Mol Genet
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Volume | 25
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Issue | 6
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Pages | 1247-54
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Date Published | 2016 Mar 15
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ISSN | 1460-2083
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URL | |
DOI | 10.1093/hmg/ddw007
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PubMed ID | 26755824
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PubMed Central ID | PMC4764200
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Grant list | T32 GM074905 / GM / NIGMS NIH HHS / United States
T32GM074905 / GM / NIGMS NIH HHS / United States
R01 DK075787 / DK / NIDDK NIH HHS / United States
U01MH094421 / MH / NIMH NIH HHS / United States
2R01DK075787 / DK / NIDDK NIH HHS / United States
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