Analysis of shared heritability in common disorders of the brain.

Science

Authors	Brainstorm Consortium Verneri Anttila Brendan Bulik-Sullivan Hilary Finucane Raymond Walters Jose Bras Laramie Duncan Valentina Escott-Price Guido Falcone Padhraig Gormley Rainer Malik Nikolaos Patsopoulos Stephan Ripke Zhi Wei Dongmei Yu Phil Lee Patrick Turley Benjamin Grenier-Boley Vincent Chouraki Yoichiro Kamatani Claudine Berr Luc Letenneur Didier Hannequin Philippe Amouyel Anne Boland Jean-François Deleuze Emmanuelle Duron Badri Vardarajan Christiane Reitz Alison Goate Matthew Huentelman M Ilyas Kamboh Eric Larson Ekaterina Rogaeva Peter St George-Hyslop Hakon Hakonarson Walter Kukull Lindsay Farrer Lisa Barnes Thomas Beach F Yesim Demirci Elizabeth Head Christine Hulette Gregory Jicha John Kauwe Jeffrey Kaye James Leverenz Allan Levey Andrew Lieberman Vernon Pankratz Wayne Poon Joseph Quinn Andrew Saykin Lon Schneider Amanda Smith Joshua Sonnen Robert Stern Vivianna Van Deerlin Linda Van Eldik Denise Harold Giancarlo Russo David Rubinsztein Anthony Bayer Magda Tsolaki Petra Proitsi Nick Fox Harald Hampel Michael Owen Simon Mead Peter Passmore Kevin Morgan Markus Nöthen Martin Rossor Michelle Lupton Per Hoffmann Johannes Kornhuber Brian Lawlor Andrew McQuillin Ammar Al-Chalabi Joshua Bis Agustin Ruiz Mercè Boada Sudha Seshadri Alexa Beiser Kenneth Rice Sven Van der Lee Philip De Jager Daniel Geschwind Matthias Riemenschneider Steffi Riedel-Heller Jerome Rotter Gerhard Ransmayr Bradley Hyman Carlos Cruchaga Montserrat Alegret Bendik Winsvold Priit Palta Kai-How Farh Ester Cuenca-León Nicholas Furlotte Tobias Kurth Lannie Ligthart Gisela Terwindt Tobias Freilinger Caroline Ran Scott Gordon Guntram Borck Hieab Adams Terho Lehtimäki Juho Wedenoja Julie Buring Markus Schürks Maria Hrafnsdottir Jouke-Jan Hottenga Brenda Penninx Ville Artto Mari Kaunisto Salli Vepsäläinen Nicholas Martin Grant Montgomery Mitja Kurki Eija Hämäläinen Hailiang Huang Jie Huang Cynthia Sandor Caleb Webber Bertram Müller-Myhsok Stefan Schreiber Veikko Salomaa Elizabeth Loehrer Hartmut Göbel Alfons Macaya Patricia Pozo-Rosich Thomas Hansen Thomas Werge Jaakko Kaprio Andres Metspalu Christian Kubisch Michel Ferrari Andrea Belin Arn van den Maagdenberg John-Anker Zwart Dorret Boomsma Nicholas Eriksson Jes Olesen Daniel Chasman Dale Nyholt Andreja Avbersek Larry Baum Samuel Berkovic Jonathan Bradfield Russell Buono Claudia Catarino Patrick Cossette Peter De Jonghe Chantal Depondt Dennis Dlugos Thomas Ferraro Jacqueline French Helle Hjalgrim Jennifer Jamnadas-Khoda Reetta Kälviäinen Wolfram Kunz Holger Lerche Costin Leu Dick Lindhout Warren Lo Daniel Lowenstein Mark McCormack Rikke Møller Anne Molloy Ping-Wing Ng Karen Oliver Michael Privitera Rodney Radtke Ann-Kathrin Ruppert Thomas Sander Steven Schachter Christoph Schankin Ingrid Scheffer Susanne Schoch Sanjay Sisodiya Philip Smith Michael Sperling Pasquale Striano Rainer Surges G Neil Thomas Frank Visscher Christopher Whelan Federico Zara Erin Heinzen Anthony Marson Felicitas Becker Hans Stroink Fritz Zimprich Thomas Gasser Raphael Gibbs Peter Heutink Maria Martinez Huw Morris Manu Sharma Mina Ryten Kin Mok Sara Pulit Steve Bevan Elizabeth Holliday John Attia Thomas Battey Giorgio Boncoraglio Vincent Thijs Wei-Min Chen Braxton Mitchell Peter Rothwell Pankaj Sharma Cathie Sudlow Astrid Vicente Hugh Markus Christina Kourkoulis Joana Pera Miriam Raffeld Scott Silliman Vesna Perica Laura Thornton Laura Huckins William Rayner Cathryn Lewis Monica Gratacos Filip Rybakowski Anna Keski-Rahkonen Anu Raevuori James Hudson Ted Reichborn-Kjennerud Palmiero Monteleone Andreas Karwautz Katrin Männik Jessica Baker Julie O'Toole Sara Trace Oliver Davis Sietske Helder Stefan Ehrlich Beate Herpertz-Dahlmann Unna Danner Annemarie van Elburg Maurizio Clementi Monica Forzan Elisa Docampo Jolanta Lissowska Joanna Hauser Alfonso Tortorella Mario Maj Fragiskos Gonidakis Konstantinos Tziouvas Hana Papezova Zeynep Yilmaz Gudrun Wagner Sarah Cohen-Woods Stefan Herms Antonio Julià Raquel Rabionet Danielle Dick Samuli Ripatti Ole Andreassen Thomas Espeseth Astri Lundervold Vidar Steen Dalila Pinto Stephen Scherer Harald Aschauer Alexandra Schosser Lars Alfredsson Leonid Padyukov Katherine Halmi James Mitchell Michael Strober Andrew Bergen Walter Kaye Jin Szatkiewicz Bru Cormand Josep Ramos-Quiroga Cristina Sánchez-Mora Marta Ribasés Miguel Casas Amaia Hervas Maria Arranz Jan Haavik Tetyana Zayats Stefan Johansson Nigel Williams Astrid Dempfle Aribert Rothenberger Jonna Kuntsi Robert Oades Tobias Banaschewski Barbara Franke Jan Buitelaar Alejandro Vasquez Alysa Doyle Andreas Reif Klaus-Peter Lesch Christine Freitag Olga Rivero Haukur Palmason Marcel Romanos Kate Langley Marcella Rietschel Stephanie Witt Soeren Dalsgaard Anders Børglum Irwin Waldman Beth Wilmot Nikolas Molly Claiton Bau Jennifer Crosbie Russell Schachar Sandra Loo James McGough Eugenio Grevet Sarah Medland Elise Robinson Lauren Weiss Elena Bacchelli Anthony Bailey Vanessa Bal Agatino Battaglia Catalina Betancur Patrick Bolton Rita Cantor Patrícia Celestino-Soper Geraldine Dawson Silvia De Rubeis Frederico Duque Andrew Green Sabine Klauck Marion Leboyer Pat Levitt Elena Maestrini Shrikant Mane Daniel De-Luca Jeremy Parr Regina Regan Abraham Reichenberg Sven Sandin Jacob Vorstman Thomas Wassink Ellen Wijsman Edwin Cook Susan Santangelo Richard Delorme Bernadette Rogé Tiago Magalhaes Dan Arking Thomas Schulze Robert Thompson Jana Strohmaier Keith Matthews Ingrid Melle Derek Morris Douglas Blackwood Andrew McIntosh Sarah Bergen Martin Schalling Stéphane Jamain Anna Maaser Sascha Fischer Céline Reinbold Janice Fullerton José Guzman-Parra Fermin Mayoral Peter Schofield Sven Cichon Thomas Mühleisen Franziska Degenhardt Johannes Schumacher Michael Bauer Philip Mitchell Elliot Gershon John Rice James Potash Peter Zandi Nick Craddock I Nicol Ferrier Martin Alda Guy Rouleau Gustavo Turecki Roel Ophoff Carlos Pato Adebayo Anjorin Eli Stahl Markus Leber Piotr Czerski Cristiana Cruceanu Ian Jones Danielle Posthuma Till Andlauer Andreas Forstner Fabian Streit Bernhard Baune Tracy Air Grant Sinnamon Naomi Wray Donald MacIntyre David Porteous Georg Homuth Margarita Rivera Jakob Grove Christel Middeldorp Ian Hickie Michele Pergadia Divya Mehta Johannes Smit Rick Jansen Eco de Geus Erin Dunn Qingqin Li Matthias Nauck Robert Schoevers Aartjan Beekman James Knowles Alexander Viktorin Paul Arnold Cathy Barr Gabriel Bedoya-Berrio O Joseph Bienvenu Helena Brentani Christie Burton Beatriz Camarena Carolina Cappi Danielle Cath Maria Cavallini Daniele Cusi Sabrina Darrow Damiaan Denys Eske Derks Andrea Dietrich Thomas Fernandez Martijn Figee Nelson Freimer Gloria Gerber Marco Grados Erica Greenberg Gregory Hanna Andreas Hartmann Matthew Hirschtritt Pieter Hoekstra Alden Huang Chaim Huyser Cornelia Illmann Michael Jenike Samuel Kuperman Bennett Leventhal Christine Lochner Gholson Lyon Fabio Macciardi Marcos Madruga-Garrido Irene Malaty Athanasios Maras Lauren McGrath Euripedes Miguel Pablo Mir Gerald Nestadt Humberto Nicolini Michael Okun Andrew Pakstis Peristera Paschou John Piacentini Christopher Pittenger Kerstin Plessen Vasily Ramensky Eliana Ramos Victor Reus Margaret Richter Mark Riddle Mary Robertson Veit Roessner Maria Rosário Jack Samuels Paul Sandor Dan Stein Fotis Tsetsos Filip Van Nieuwerburgh Sarah Weatherall Jens Wendland Tomasz Wolanczyk Yulia Worbe Gwyneth Zai Fernando Goes Nicole McLaughlin Paul Nestadt Hans-Jörgen Grabe Christel Depienne Anuar Konkashbaev Nuria Lanzagorta Ana Valencia-Duarte Elvira Bramon Nancy Buccola Wiepke Cahn Murray Cairns Siow Chong David Cohen Benedicto Crespo-Facorro James Crowley Michael Davidson Lynn DeLisi Timothy Dinan Gary Donohoe Elodie Drapeau Jubao Duan Lieuwe Haan David Hougaard Sena Karachanak-Yankova Andrey Khrunin Janis Klovins Vaidutis Kučinskas Jimmy Keong Svetlana Limborska Carmel Loughland Jouko Lönnqvist Brion Maher Manuel Mattheisen Colm McDonald Kieran Murphy Igor Nenadic Jim Van Os Christos Pantelis Michele Pato Tracey Petryshen Digby Quested Panos Roussos Alan Sanders Ulrich Schall Sibylle Schwab Kang Sim Hon-Cheong So Elisabeth Stögmann Mythily Subramaniam Draga Toncheva John Waddington James Walters Mark Weiser Wei Cheng Robert Cloninger David Curtis Pablo Gejman Frans Henskens Morten Mattingsdal Sang-Yun Oh Rodney Scott Bradley Webb Gerome Breen Claire Churchhouse Cynthia Bulik Mark Daly Martin Dichgans Stephen Faraone Rita Guerreiro Peter Holmans Kenneth Kendler Bobby Koeleman Carol Mathews Alkes Price Jeremiah Scharf Pamela Sklar Julie Williams Nicholas Wood Chris Cotsapas Aarno Palotie Jordan Smoller Patrick Sullivan Jonathan Rosand Aiden Corvin Benjamin Neale Jonathan Schott Richard Anney Josephine Elia Maria Grigoroiu-Serbanescu Howard Edenberg Robin Murray
Keywords	Humans Phenotype Risk Factors Genome-Wide Association Study Genetic Variation Mental Disorders Quantitative Trait, Heritable Brain Diseases
Abstract	Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
Year of Publication	2018
Journal	Science
Volume	360
Issue	6395
Date Published	2018 06 22
ISSN	1095-9203
DOI	10.1126/science.aap8757
PubMed ID	29930110
PubMed Central ID	PMC6097237
Links
Grant list	K07 AG043587 / AG / NIA NIH HHS / United States 203249/Z/16/Z / WT_ / Wellcome Trust / United Kingdom R01 MH100027 / MH / NIMH NIH HHS / United States P01 AG026276 / AG / NIA NIH HHS / United States MR/N008324/1 / MRC_ / Medical Research Council / United Kingdom P30 AG021342 / AG / NIA NIH HHS / United States P30 AG008017 / AG / NIA NIH HHS / United States P30 AG010161 / AG / NIA NIH HHS / United States MR/R024804/1 / MRC_ / Medical Research Council / United Kingdom R01 AG041718 / AG / NIA NIH HHS / United States G0401207 / MRC_ / Medical Research Council / United Kingdom R01 NS017950 / NS / NINDS NIH HHS / United States G0800637 / MRC_ / Medical Research Council / United Kingdom MR/L501529/1 / MRC_ / Medical Research Council / United Kingdom R01 AG054076 / AG / NIA NIH HHS / United States K01 MH109782 / MH / NIMH NIH HHS / United States UL1 TR002369 / TR / NCATS NIH HHS / United States R25 MH077823 / MH / NIMH NIH HHS / United States MR/L010305/1 / MRC_ / Medical Research Council / United Kingdom Z99 AG999999 / ImNIH / Intramural NIH HHS / United States MR/L501554/1 / MRC_ / Medical Research Council / United Kingdom MC_UU_00024/1 / MRC_ / Medical Research Council / United Kingdom U01 AG016976 / AG / NIA NIH HHS / United States PDA/02/06/016 / DH_ / Department of Health / United Kingdom P01 AG003991 / AG / NIA NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States P50 AG005136 / AG / NIA NIH HHS / United States G0300189 / MRC_ / Medical Research Council / United Kingdom U01 MH109536 / MH / NIMH NIH HHS / United States R01 MH106490 / MH / NIMH NIH HHS / United States R01 MH115961 / MH / NIMH NIH HHS / United States P50 AG005133 / AG / NIA NIH HHS / United States T32 MH076694 / MH / NIMH NIH HHS / United States R01 MH085548 / MH / NIMH NIH HHS / United States G0901310 / MRC_ / Medical Research Council / United Kingdom U24 MH068457 / MH / NIMH NIH HHS / United States MR/P005748/1 / MRC_ / Medical Research Council / United Kingdom R00 MH101367 / MH / NIMH NIH HHS / United States J-0901 / PUK_ / Parkinson's UK / United Kingdom MC_G1000735 / MRC_ / Medical Research Council / United Kingdom UKDRI-2002 / MRC_ / Medical Research Council / United Kingdom ALCHALABI-DOBSON/APR14/829-791 / MNDA_ / Motor Neurone Disease Association / United Kingdom U01 AG052409 / AG / NIA NIH HHS / United States R01 AG030653 / AG / NIA NIH HHS / United States R01 MH107649 / MH / NIMH NIH HHS / United States R01 MH092293 / MH / NIMH NIH HHS / United States P30 AG010129 / AG / NIA NIH HHS / United States U01 MH094432 / MH / NIMH NIH HHS / United States MR/L023784/2 / MRC_ / Medical Research Council / United Kingdom MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom U01 AG049505 / AG / NIA NIH HHS / United States