Dataset Information

Analysis of shared heritability in common disorders of the brain.

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.

SUBMITTER: Brainstorm Consortium

PROVIDER: S-EPMC6097237 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Analysis of shared heritability in common disorders of the brain.

Anttila Verneri V Bulik-Sullivan Brendan B Finucane Hilary K HK Walters Raymond K RK Bras Jose J Duncan Laramie L Escott-Price Valentina V Falcone Guido J GJ Gormley Padhraig P Malik Rainer R Patsopoulos Nikolaos A NA Ripke Stephan S Wei Zhi Z Yu Dongmei D Lee Phil H PH Lee Phil H PH Turley Patrick P Grenier-Boley Benjamin B Chouraki Vincent V Kamatani Yoichiro Y Berr Claudine C Letenneur Luc L Hannequin Didier D Amouyel Philippe P Boland Anne A Deleuze Jean-François JF Duron Emmanuelle E Vardarajan Badri N BN Reitz Christiane C Goate Alison M AM Huentelman Matthew J MJ Kamboh M Ilyas MI Larson Eric B EB Rogaeva Ekaterina E St George-Hyslop Peter P Hakonarson Hakon H Kukull Walter A WA Farrer Lindsay A LA Barnes Lisa L LL Beach Thomas G TG Demirci F Yesim FY Head Elizabeth E Hulette Christine M CM Jicha Gregory A GA Kauwe John S K JSK Kaye Jeffrey A JA Leverenz James B JB Levey Allan I AI Lieberman Andrew P AP Pankratz Vernon S VS Poon Wayne W WW Quinn Joseph F JF Saykin Andrew J AJ Schneider Lon S LS Smith Amanda G AG Sonnen Joshua A JA Stern Robert A RA Van Deerlin Vivianna M VM Van Eldik Linda J LJ Harold Denise D Russo Giancarlo G Rubinsztein David C DC Bayer Anthony A Tsolaki Magda M Proitsi Petra P Fox Nick C NC Hampel Harald H Owen Michael J MJ Mead Simon S Passmore Peter P Morgan Kevin K Nöthen Markus M MM Rossor Martin M Lupton Michelle K MK Hoffmann Per P Kornhuber Johannes J Lawlor Brian B McQuillin Andrew A Al-Chalabi Ammar A Bis Joshua C JC Ruiz Agustin A Boada Mercè M Seshadri Sudha S Beiser Alexa A Rice Kenneth K van der Lee Sven J SJ De Jager Philip L PL Geschwind Daniel H DH Riemenschneider Matthias M Riedel-Heller Steffi S Rotter Jerome I JI Ransmayr Gerhard G Hyman Bradley T BT Cruchaga Carlos C Alegret Montserrat M Winsvold Bendik B Palta Priit P Farh Kai-How KH Cuenca-Leon Ester E Furlotte Nicholas N Kurth Tobias T Ligthart Lannie L Terwindt Gisela M GM Freilinger Tobias T Ran Caroline C Gordon Scott D SD Borck Guntram G Adams Hieab H H HHH Lehtimäki Terho T Wedenoja Juho J Buring Julie E JE Schürks Markus M Hrafnsdottir Maria M Hottenga Jouke-Jan JJ Penninx Brenda B Artto Ville V Kaunisto Mari M Vepsäläinen Salli S Martin Nicholas G NG Montgomery Grant W GW Kurki Mitja I MI Hämäläinen Eija E Huang Hailiang H Huang Jie J Sandor Cynthia C Webber Caleb C Muller-Myhsok Bertram B Schreiber Stefan S Salomaa Veikko V Loehrer Elizabeth E Göbel Hartmut H Macaya Alfons A Pozo-Rosich Patricia P Hansen Thomas T Werge Thomas T Kaprio Jaakko J Metspalu Andres A Kubisch Christian C Ferrari Michel D MD Belin Andrea C AC van den Maagdenberg Arn M J M AMJM Zwart John-Anker JA Boomsma Dorret D Eriksson Nicholas N Olesen Jes J Chasman Daniel I DI Nyholt Dale R DR Avbersek Andreja A Baum Larry L Berkovic Samuel S Bradfield Jonathan J Buono Russell J RJ Catarino Claudia B CB Cossette Patrick P De Jonghe Peter P Depondt Chantal C Dlugos Dennis D Ferraro Thomas N TN French Jacqueline J Hjalgrim Helle H Jamnadas-Khoda Jennifer J Kälviäinen Reetta R Kunz Wolfram S WS Lerche Holger H Leu Costin C Lindhout Dick D Lo Warren W Lowenstein Daniel D McCormack Mark M Møller Rikke S RS Molloy Anne A Ng Ping-Wing PW Oliver Karen K Privitera Michael M Radtke Rodney R Ruppert Ann-Kathrin AK Sander Thomas T Schachter Steven S Schankin Christoph C Scheffer Ingrid I Schoch Susanne S Sisodiya Sanjay M SM Smith Philip P Sperling Michael M Striano Pasquale P Surges Rainer R Thomas G Neil GN Visscher Frank F Whelan Christopher D CD Zara Federico F Heinzen Erin L EL Marson Anthony A Becker Felicitas F Stroink Hans H Zimprich Fritz F Gasser Thomas T Gibbs Raphael R Heutink Peter P Martinez Maria M Morris Huw R HR Sharma Manu M Ryten Mina M Mok Kin Y KY Pulit Sara S Bevan Steve S Holliday Elizabeth E Attia John J Battey Thomas T Boncoraglio Giorgio G Thijs Vincent V Chen Wei-Min WM Mitchell Braxton B Rothwell Peter P Sharma Pankaj P Sudlow Cathie C Vicente Astrid A Markus Hugh H Kourkoulis Christina C Pera Joana J Raffeld Miriam M Silliman Scott S Boraska Perica Vesna V Thornton Laura M LM Huckins Laura M LM William Rayner N N Lewis Cathryn M CM Gratacos Monica M Rybakowski Filip F Keski-Rahkonen Anna A Raevuori Anu A Hudson James I JI Reichborn-Kjennerud Ted T Monteleone Palmiero P Karwautz Andreas A Mannik Katrin K Baker Jessica H JH O'Toole Julie K JK Trace Sara E SE Davis Oliver S P OSP Helder Sietske G SG Ehrlich Stefan S Herpertz-Dahlmann Beate B Danner Unna N UN van Elburg Annemarie A AA Clementi Maurizio M Forzan Monica M Docampo Elisa E Lissowska Jolanta J Hauser Joanna J Tortorella Alfonso A Maj Mario M Gonidakis Fragiskos F Tziouvas Konstantinos K Papezova Hana H Yilmaz Zeynep Z Wagner Gudrun G Cohen-Woods Sarah S Herms Stefan S Julià Antonio A Rabionet Raquel R Dick Danielle M DM Ripatti Samuli S Andreassen Ole A OA Espeseth Thomas T Lundervold Astri J AJ Steen Vidar M VM Pinto Dalila D Scherer Stephen W SW Aschauer Harald H Schosser Alexandra A Alfredsson Lars L Padyukov Leonid L Halmi Katherine A KA Mitchell James J Strober Michael M Bergen Andrew W AW Kaye Walter W Szatkiewicz Jin Peng JP Cormand Bru B Ramos-Quiroga Josep Antoni JA Sánchez-Mora Cristina C Ribasés Marta M Casas Miguel M Hervas Amaia A Arranz Maria Jesús MJ Haavik Jan J Zayats Tetyana T Johansson Stefan S Williams Nigel N Dempfle Astrid A Rothenberger Aribert A Kuntsi Jonna J Oades Robert D RD Banaschewski Tobias T Franke Barbara B Buitelaar Jan K JK Arias Vasquez Alejandro A Doyle Alysa E AE Reif Andreas A Lesch Klaus-Peter KP Freitag Christine C Rivero Olga O Palmason Haukur H Romanos Marcel M Langley Kate K Rietschel Marcella M Witt Stephanie H SH Dalsgaard Soeren S Børglum Anders D AD Waldman Irwin I Wilmot Beth B Molly Nikolas N Bau Claiton H D CHD Crosbie Jennifer J Schachar Russell R Loo Sandra K SK McGough James J JJ Grevet Eugenio H EH Medland Sarah E SE Robinson Elise E Weiss Lauren A LA Bacchelli Elena E Bailey Anthony A Bal Vanessa V Battaglia Agatino A Betancur Catalina C Bolton Patrick P Cantor Rita R Celestino-Soper Patrícia P Dawson Geraldine G De Rubeis Silvia S Duque Frederico F Green Andrew A Klauck Sabine M SM Leboyer Marion M Levitt Pat P Maestrini Elena E Mane Shrikant S De-Luca Daniel Moreno- DM Parr Jeremy J Regan Regina R Reichenberg Abraham A Sandin Sven S Vorstman Jacob J Wassink Thomas T Wijsman Ellen E Cook Edwin E Santangelo Susan S Delorme Richard R Rogé Bernadette B Magalhaes Tiago T Arking Dan D Schulze Thomas G TG Thompson Robert C RC Strohmaier Jana J Matthews Keith K Melle Ingrid I Morris Derek D Blackwood Douglas D McIntosh Andrew A Bergen Sarah E SE Schalling Martin M Jamain Stéphane S Maaser Anna A Fischer Sascha B SB Reinbold Céline S CS Fullerton Janice M JM Guzman-Parra José J Mayoral Fermin F Schofield Peter R PR Cichon Sven S Mühleisen Thomas W TW Degenhardt Franziska F Schumacher Johannes J Bauer Michael M Mitchell Philip B PB Gershon Elliot S ES Rice John J Potash James B JB Zandi Peter P PP Craddock Nick N Ferrier I Nicol IN Alda Martin M Rouleau Guy A GA Turecki Gustavo G Ophoff Roel R Pato Carlos C Anjorin Adebayo A Stahl Eli E Leber Markus M Czerski Piotr M PM Cruceanu Cristiana C Jones Ian R IR Posthuma Danielle D Andlauer Till F M TFM Forstner Andreas J AJ Streit Fabian F Baune Bernhard T BT Air Tracy T Sinnamon Grant G Wray Naomi R NR MacIntyre Donald J DJ Porteous David D Homuth Georg G Rivera Margarita M Grove Jakob J Middeldorp Christel M CM Hickie Ian I Pergadia Michele M Mehta Divya D Smit Johannes H JH Jansen Rick R de Geus Eco E Dunn Erin E Li Qingqin S QS Nauck Matthias M Schoevers Robert A RA Beekman Aartjan Tf AT Knowles James A JA Viktorin Alexander A Arnold Paul P Barr Cathy L CL Bedoya-Berrio Gabriel G Bienvenu O Joseph OJ Brentani Helena H Burton Christie C Camarena Beatriz B Cappi Carolina C Cath Danielle D Cavallini Maria M Cusi Daniele D Darrow Sabrina S Denys Damiaan D Derks Eske M EM Dietrich Andrea A Fernandez Thomas T Figee Martijn M Freimer Nelson N Gerber Gloria G Grados Marco M Greenberg Erica E Hanna Gregory L GL Hartmann Andreas A Hirschtritt Matthew E ME Hoekstra Pieter J PJ Huang Alden A Huyser Chaim C Illmann Cornelia C Jenike Michael M Kuperman Samuel S Leventhal Bennett B Lochner Christine C Lyon Gholson J GJ Macciardi Fabio F Madruga-Garrido Marcos M Malaty Irene A IA Maras Athanasios A McGrath Lauren L Miguel Eurípedes C EC Mir Pablo P Nestadt Gerald G Nicolini Humberto H Okun Michael S MS Pakstis Andrew A Paschou Peristera P Piacentini John J Pittenger Christopher C Plessen Kerstin K Ramensky Vasily V Ramos Eliana M EM Reus Victor V Richter Margaret A MA Riddle Mark A MA Robertson Mary M MM Roessner Veit V Rosário Maria M Samuels Jack F JF Sandor Paul P Stein Dan J DJ Tsetsos Fotis F Van Nieuwerburgh Filip F Weatherall Sarah S Wendland Jens R JR Wolanczyk Tomasz T Worbe Yulia Y Zai Gwyneth G Goes Fernando S FS McLaughlin Nicole N Nestadt Paul S PS Grabe Hans-Jorgen HJ Depienne Christel C Konkashbaev Anuar A Lanzagorta Nuria N Valencia-Duarte Ana A Bramon Elvira E Buccola Nancy N Cahn Wiepke W Cairns Murray M Chong Siow A SA Cohen David D Crespo-Facorro Benedicto B Crowley James J Davidson Michael M DeLisi Lynn L Dinan Timothy T Donohoe Gary G Drapeau Elodie E Duan Jubao J Haan Lieuwe L Hougaard David D Karachanak-Yankova Sena S Khrunin Andrey A Klovins Janis J Kučinskas Vaidutis V Lee Chee Keong Jimmy J Limborska Svetlana S Loughland Carmel C Lönnqvist Jouko J Maher Brion B Mattheisen Manuel M McDonald Colm C Murphy Kieran C KC Nenadic Igor I van Os Jim J Pantelis Christos C Pato Michele M Petryshen Tracey T Quested Digby D Roussos Panos P Sanders Alan R AR Schall Ulrich U Schwab Sibylle G SG Sim Kang K So Hon-Cheong HC Stögmann Elisabeth E Subramaniam Mythily M Toncheva Draga D Waddington John J Walters James J Weiser Mark M Cheng Wei W Cloninger Robert R Curtis David D Gejman Pablo V PV Henskens Frans F Mattingsdal Morten M Oh Sang-Yun SY Scott Rodney R Webb Bradley B Breen Gerome G Churchhouse Claire C Bulik Cynthia M CM Daly Mark M Dichgans Martin M Faraone Stephen V SV Guerreiro Rita R Holmans Peter P Kendler Kenneth S KS Koeleman Bobby B Mathews Carol A CA Price Alkes A Scharf Jeremiah J Sklar Pamela P Williams Julie J Wood Nicholas W NW Cotsapas Chris C Palotie Aarno A Smoller Jordan W JW Sullivan Patrick P Rosand Jonathan J Corvin Aiden A Neale Benjamin M BM Schott Jonathan M JM Anney Richard R Elia Josephine J Grigoroiu-Serbanescu Maria M Edenberg Howard J HJ Murray Robin R

Science (New York, N.Y.) 20180601 6395

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 ...[more]

PMID: 29930110

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Project description:Psychiatric disorders and common epilepsies are heritable disorders with a high comorbidity and overlapping symptoms. However, the causative mechanisms underlying this relationship are poorly understood. Here we aimed to identify overlapping genetic loci between epilepsy and psychiatric disorders to gain a better understanding of their comorbidity and shared clinical features. We analysed genome-wide association study data for all epilepsies (n = 44 889), genetic generalized epilepsy (n = 33 446), focal epilepsy (n = 39 348), schizophrenia (n = 77 096), bipolar disorder (n = 406 405), depression (n = 500 199), attention deficit hyperactivity disorder (n = 53 293) and autism spectrum disorder (n = 46 350). First, we applied the MiXeR tool to estimate the total number of causal variants influencing the disorders. Next, we used the conjunctional false discovery rate statistical framework to improve power to discover shared genomic loci. Additionally, we assessed the validity of the findings in independent cohorts, and functionally characterized the identified loci. The epilepsy phenotypes were considerably less polygenic (1.0 K to 3.4 K causal variants) than the psychiatric disorders (5.6 K to 13.9 K causal variants), with focal epilepsy being the least polygenic (1.0 K variants), and depression having the highest polygenicity (13.9 K variants). We observed cross-trait genetic enrichment between genetic generalized epilepsy and all psychiatric disorders and between all epilepsies and schizophrenia and depression. Using conjunctional false discovery rate analysis, we identified 40 distinct loci jointly associated with epilepsies and psychiatric disorders at conjunctional false discovery rate <0.05, four of which were associated with all epilepsies and 39 with genetic generalized epilepsy. Most epilepsy risk loci were shared with schizophrenia (n = 31). Among the identified loci, 32 were novel for genetic generalized epilepsy, and two were novel for all epilepsies. There was a mixture of concordant and discordant allelic effects in the shared loci. The sign concordance of the identified variants was highly consistent between the discovery and independent datasets for all disorders, supporting the validity of the findings. Gene-set analysis for the shared loci between schizophrenia and genetic generalized epilepsy implicated biological processes related to cell cycle regulation, protein phosphatase activity, and membrane and vesicle function; the gene-set analyses for the other loci were underpowered. The extensive genetic overlap with mixed effect directions between psychiatric disorders and common epilepsies demonstrates a complex genetic relationship between these disorders, in line with their bi-directional relationship, and indicates that overlapping genetic risk may contribute to shared pathophysiological and clinical features between epilepsy and psychiatric disorders.

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Analysis of shared heritability in common disorders of the brain.

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Analysis of shared heritability in common disorders of the brain.

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