Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders
Authors: Andlauer Till F. M. , Guzman-Parra Jose , Streit Fabian , Strohmaier Jana , González Maria José , Gil Flores Susana , Cabaleiro Fabeiro Francisco J. , del Río Noriega Francisco , Perez Fermin Perez , Haro González Jesus , Orozco Diaz Guillermo , de Diego-Otero Yolanda , Moreno-Küstner Berta , Auburger Georg , Degenhardt Franziska , Heilmann-Heimbach Stefanie , Herms Stefan , Hoffmann Per , Frank Josef , Foo Jerome C. , Treutlein Jens , Witt Stephanie H. , Cichon Sven , Kogevinas Manolis ,   Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Stahl Eli A , Breen Gerome , Forstner Andreas J , McQuillin Andrew , Ripke Stephan , Trubetskoy Vassily , Mattheisen Manuel , Wang Yunpeng , Coleman Jonathan R I , Gaspar Héléna A , de Leeuw Christiaan A , Steinberg Stacy , Pavlides Jennifer M Whitehead , Trzaskowski Maciej , Pers Tune H , Holmans Peter A , Abbott Liam , Agerbo Esben , Akil Huda , Albani Diego , Alliey-Rodriguez Ney , Als Thomas D , Anjorin Adebayo , Antilla Verneri , Awasthi Swapnil , Badner Judith A , Bækvad-Hansen Marie , Barchas Jack D , Bass Nicholas , Bauer Michael , Belliveau Richard , Bergen Sarah E , Pedersen Carsten Bøcker , Bøen Erlend , Boks Marco , Boocock James , Budde Monika , Bunney William , Burmeister Margit , Bybjerg-Grauholm Jonas , Byerley William , Casas Miquel , Cerrato Felecia , Cervantes Pablo , Chambert Kimberly , Charney Alexander W , Chen Danfeng , Churchhouse Claire , Clarke Toni-Kim , Coryell William , Craig David W , Cruceanu Cristiana , Czerski Piotr M , Dale Anders M , de Jong Simone , Degenhardt Franziska , Del-Favero Jurgen , DePaulo J Raymond , Djurovic Srdjan , Dobbyn Amanda L , Dumont Ashley , Elvsåshagen Torbjørn , Escott-Price Valentina , Fan Chun Chieh , Fischer Sascha B , Flickinger Matthew , Foroud Tatiana M , Forty Liz , Frank Josef , Fraser Christine , Freimer Nelson B , Frisén Louise , Gade Katrin , Gage Diane , Garnham Julie , Giambartolomei Claudia , Pedersen Marianne Giørtz , Goldstein Jaqueline , Gordon Scott D , Gordon-Smith Katherine , Green Elaine K , Green Melissa J , Greenwood Tiffany A , Grove Jakob , Guan Weihua , Parra José Guzman , Hamshere Marian L , Hautzinger Martin , Heilbronner Urs , Herms Stefan , Hipolito Maria , Hoffmann Per , Holland Dominic , Huckins Laura , Jamain Stéphane , Johnson Jessica S , Juréus Anders , Kandaswamy Radhika , Karlsson Robert , Kennedy James L , Kittel-Schneider Sarah , Knowles James A , Kogevinas Manolis , Koller Anna C , Kupka Ralph , Lavebratt Catharina , Lawrence Jacob , Lawson William B , Leber Markus , Lee Phil H , Levy Shawn E , Li Jun Z , Liu Chunyu , Lucae Susanne , Maaser Anna , MacIntyre Donald J , Mahon Pamela B , Maier Wolfgang , Martinsson Lina , McCarroll Steve , McGuffin Peter , McInnis Melvin G , McKay James D , Medeiros Helena , Medland Sarah E , Meng Fan , Milani Lili , Montgomery Grant W , Morris Derek W , Mühleisen Thomas W , Mullins Niamh , Nguyen Hoang , Nievergelt Caroline M , Adolfsson Annelie Nordin , Nwulia Evaristus A , O’Donovan Claire , Loohuis Loes M Olde , Ori Anil P S , Oruc Lilijana , Ösby Urban , Perlis Roy H , Perry Amy , Pfennig Andrea , Potash James B , Purcell Shaun M , Regeer Eline J , Reif Andreas , Reinbold Céline S , Rice John P , Richards Alexander L , Rivas Fabio , Rivera Margarita , Roussos Panos , Ruderfer Douglas M , Ryu Euijung , Sánchez-Mora Cristina , Schatzberg Alan F , Scheftner William A , Schork Nicholas J , Weickert Cynthia Shannon , Shehktman Tatyana , Shilling Paul D , Sigurdsson Engilbert , Slaney Claire , Smeland Olav B , Sobell Janet L , Hansen Christine Søholm , Spijker Anne T , Clair David St , Steffens Michael , Strauss John S , Streit Fabian , Strohmaier Jana , Szelinger Szabolcs , Thompson Robert C , EThorgeirsson Thorgeir , Treutlein Jens , Vedde Helmut , Wang Weiqing , Watson Stanley J , Weickert Thomas W , Witt Stephanie H , Xi Simon , Xu Wei , Young Allan H , Zandi Peter , Zhang Peng , Zollner Sebastian , Adolfsson Rolf , Agartz Ingrid , Alda Martin , Backlund Lena , Baune Bernhard T , Bellivier Frank , Berrettini Wade H , Biernacka Joanna M , Blackwood Douglas H R , Boehnke Michael , Børglum Anders D , Corvin Aiden , Craddock Nicholas , Daly Mark J , Dannlowski Udo , Esko Tõnu , Etain Bruno , Frye Mark , Fullerton Janice M , Gershon Elliot S , Gill Michael , Goes Fernando , Grigoroiu-Serbanescu Maria , Hauser Joanna , Hougaard David M , Hultman Christina M , Jones Ian , Jones Lisa A , Kahn René S , Kirov George , Landén Mikael , Leboyer Marion , Lewis Cathryn M , Li Qingqin S , Lissowska Jolanta , Martin Nicholas G , Mayoral Fermin , McElroy Susan L , McIntosh Andrew M , McMahon Francis J , Melle Ingrid , Metspalu Andres , Mitchell Philip B , Morken Gunnar , Mors Ole , Mortensen Preben Bo , Müller-Myhsok Bertram , Myers Richard M , Neale Benjamin M , Nimgaonkar Vishwajit , Nordentoft Merete , Nöthen Markus M , O’Donovan Michael C , Oedegaard Ketil J , Owen Michael J , Paciga Sara A , Pato Carlos , Pato Michele T , Posthuma Danielle , Ramos-Quiroga Josep Antoni , Ribasés Marta , Rietschel Marcella , Rouleau Guy A , Schalling Martin , Schofield Peter R , Schulze Thomas G , Serretti Alessandro , Smoller Jordan W , Stefansson Hreinn , Stefansson Kari , Stordal Eystein , Sullivan Patrick F , Turecki Gustavo , Vaaler Arne E , Vieta Eduard , Vincent John B , Werge Thomas , Nurnberger John I , Wray Naomi R , Florio Arianna Di , Edenberg Howard J , Cichon Sven , Ophoff Roel A , Scott Laura J , Andreassen Ole A , Kelsoe John , Sklar Pamela ,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Wray Naomi R , Ripke Stephan , Mattheisen Manuel , Trzaskowski Maciej , Byrne Enda M , Abdellaoui Abdel , Adams Mark J , Agerbo Esben , Air Tracy M , Andlauer Till F M , Bacanu Silviu-Alin , Bækvad-Hansen Marie , Beekman Aartjan T F , Bigdeli Tim B , Binder Elisabeth B , Bryois Julien , Buttenschøn Henriette N , Bybjerg-Grauholm Jonas , Cai Na , Castelao Enrique , Christensen Jane Hvarregaard , Clarke Toni-Kim , Coleman Jonathan R I , Colodro-Conde Lucía , Couvy-Duchesne Baptiste , Craddock Nick , Crawford Gregory E , Davies Gail , Deary Ian J , Degenhardt Franziska , Derks Eske M , Direk Nese , Dolan Conor V , Dunn Erin C , Eley Thalia C , Escott-Price Valentina , Kiadeh Farnush Farhadi Hassan , Finucane Hilary K , Foo Jerome C , Forstner Andreas J , Frank Josef , Gaspar Héléna A , Gill Michael , Goes Fernando S , Gordon Scott D , Grove Jakob , Hall Lynsey S , Hansen Christine Søholm , Hansen Thomas F , Herms Stefan , Hickie Ian B , Hoffmann Per , Homuth Georg , Horn Carsten , Hottenga Jouke-Jan , Hougaard David M , Howard David M , Ising Marcus , Jansen Rick , Jones Ian , Jones Lisa A , Jorgenson Eric , Knowles James A , Kohane Isaac S , Kraft Julia , Kretzschmar Warren W. , Kutalik Zoltán , Li Yihan , Lind Penelope A , MacIntyre Donald J , MacKinnon Dean F , Maier Robert M , Maier Wolfgang , Marchini Jonathan , Mbarek Hamdi , McGrath Patrick , McGuffin Peter , Medland Sarah E , Mehta Divya , Middeldorp Christel M , Mihailov Evelin , Milaneschi Yuri , Milani Lili , Mondimore Francis M , Montgomery Grant W , Mostafavi Sara , Mullins Niamh , Nauck Matthias , Ng Bernard , Nivard Michel G , Nyholt Dale R , O’Reilly Paul F , Oskarsson Hogni , Owen Michael J , Painter Jodie N , Pedersen Carsten Bøcker , Pedersen Marianne Giørtz , Peterson Roseann E , Pettersson Erik , Peyrot Wouter J , Pistis Giorgio , Posthuma Danielle , Quiroz Jorge A , Qvist Per , Rice John P , Riley Brien P. , Rivera Margarita , Mirza Saira Saeed , Schoevers Robert , Schulte Eva C , Shen Ling , Shi Jianxin , Shyn Stanley I , Sigurdsson Engilbert , Sinnamon Grant C B , Smit Johannes H , Smith Daniel J , Stefansson Hreinn , Steinberg Stacy , Streit Fabian , Strohmaier Jana , Tansey Katherine E , Teismann Henning , Teumer Alexander , Thompson Wesley , Thomson Pippa A , Thorgeirsson Thorgeir E , Traylor Matthew , Treutlein Jens , Trubetskoy Vassily , Uitterlinden André G , Umbricht Daniel , Van der Auwera Sandra , van Hemert Albert M , Viktorin Alexander , Visscher Peter M , Wang Yunpeng , Webb Bradley T. , Weinsheimer Shantel Marie , Wellmann Jürgen , Willemsen Gonneke , Witt Stephanie H , Wu Yang , Xi Hualin S , Yang Jian , Zhang Futao , Arolt Volker , Baune Bernhard T , Berger Klaus , Boomsma Dorret I , Cichon Sven , Dannlowski Udo , de Geus E J C , DePaulo J Raymond , Domenici Enrico , Domschke Katharina , Esko Tõnu , Grabe Hans J , Hamilton Steven P , Hayward Caroline , Heath Andrew C , Kendler Kenneth S , Kloiber Stefan , Lewis Glyn , Li Qingqin S , Lucae Susanne , Madden Pamela A F , Magnusson Patrik K , Martin Nicholas G , McIntosh Andrew M , Metspalu Andres , Mors Ole , Mortensen Preben Bo , Müller-Myhsok Bertram , Nordentoft Merete , Nöthen Markus M , O’Donovan Michael C , Paciga Sara A , Pedersen Nancy L , Penninx Brenda W J H , Perlis Roy H , Porteous David J , Potash James B , Preisig Martin , Rietschel Marcella , Schaefer Catherine , Schulze Thomas G , Smoller Jordan W , Stefansson Kari , Tiemeier Henning , Uher Rudolf , Völzke Henry , Weissman Myrna M , Werge Thomas , Lewis Cathryn M , Levinson Douglas F , Breen Gerome , Børglum Anders D , Sullivan Patrick F , Rivas Fabio , Mayoral Fermín , Müller-Myhsok Bertram , Forstner Andreas J. , Nöthen Markus M. , Rietschel Marcella 
Published: November 2019

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.