Genomics yields biological and phenotypic insights into bipolar disorder

O'Connell K. S.;Koromina M.;van der Veen T.;Boltz T.;David F. S.;Yang J. M. K.;Lin K. H.;Wang X.;Coleman J. R. I.;Mitchell B. L.;McGrouther C. C.;Rangan A. V.;Lind P. A.;Koch E.;Harder A.;Parker N.;Bendl J.;Adorjan K.;Agerbo E.;Albani D.;Alemany S.;Alliey-Rodriguez N.;Als T. D.;Andlauer T. F. M.;Antoniou A.;Ask H.;Bass N.;Bauer M.;Beins E. C.;Bigdeli T. B.;Pedersen C. B.;Boks M. P.;Børte S.;Bosch R.;Brum M.;Brumpton B. M.;Brunkhorst-Kanaan N.;Budde M.;Bybjerg-Grauholm J.;Byerley W.;Cabana-Domínguez J.;Cairns M. J.;Carpiniello B.

Writing - Review & Editing

;Casas M.;Cervantes P.;Chatzinakos C.;Chen H. C.;Clarence T.;Clarke T. K.;Claus I.;Coombes B.;Corfield E. C.;Cruceanu C.;Cuellar-Barboza A.;Czerski P. M.;Dafnas K.;Dale A. M.;Dalkner N.;Degenhardt F.;DePaulo J. R.;Djurovic S.;Drange O. K.;Escott-Price V.;Fanous A. H.;Fellendorf F. T.;Ferrier I. N.;Forty L.;Frank J.;Frei O.;Freimer N. B.;Fullard J. F.;Garnham J.;Gizer I. R.;Gordon S. D.;Gordon-Smith K.;Greenwood T. A.;Grove J.;Guzman-Parra J.;Ha T. H.;Hahn T.;Haraldsson M.;Hautzinger M.;Havdahl A.;Heilbronner U.;Hellgren D.;Herms S.;Hickie I. B.;Hoffmann P.;Holmans P. A.;Huang M. C.;Ikeda M.;Jamain S.;Johnson J. S.;Jonsson L.;Kalman J. L.;Kamatani Y.;Kennedy J. L.;Kim E.;Kim J.;Kittel-Schneider S.;Kennedy J. L.;Manolis Kogevinas;Thorsten M. Kranz;Kristi Krebs;Steven A. Kushner;Catharina Lavebratt;Jacob Lawrence;Markus Leber;Heon-Jeong Lee;Calwing Liao;Susanne Lucae;Martin Lundberg;Donald J. MacIntyre;Wolfgang Maier;Adam X. Maihofer;Dolores Malaspina;Mirko Manchia

Writing - Review & Editing

;Eirini Maratou;Lina Martinsson;Manuel Mattheisen;Nathaniel W. McGregor;Melvin G. McInnis;James D. McKay;Helena Medeiros;Andreas Meyer-Lindenberg;Vincent Millischer;Derek W. Morris;Paraskevi Moutsatsou;Thomas W. Mühleisen;Claire O’Donovan;Catherine M. Olsen;Georgia Panagiotaropoulou;Sergi Papiol;Antonio F. Pardiñas;Hye Youn Park;Amy Perry;Andrea Pfennig;Claudia Pisanu

Writing - Review & Editing

;James B. Potash;Digby Quested;Mark H. Rapaport;Eline J. Regeer;John P. Rice;Margarita Rivera;Eva C. Schulte;Fanny Senner;Alexey Shadrin;Paul D. Shilling;Engilbert Sigurdsson;Lisa Sindermann;Lea Sirignano;Dan Siskind;Claire Slaney;Laura G. Sloofman;Olav B. Smeland;Daniel J. Smith;Janet L. Sobell;Maria Soler Artigas;Dan J. Stein;Frederike Stein;Mei-Hsin Su;Heejong Sung;Beata Świątkowska;Chikashi Terao;Markos Tesfaye;Martin Tesli;Thorgeir E. Thorgeirsson;Jackson G. Thorp;Claudio Toma;Leonardo Tondo;Paul A. Tooney;Shih-Jen Tsai;Evangelia Eirini Tsermpini;Marquis P. Vawter;Helmut Vedder;Annabel Vreeker;James T. R. Walters;Bendik S. Winsvold;Stephanie H. Witt;Hong-Hee Won;Robert Ye;Allan H. Young;Peter P. Zandi;Lea Zillich;Rolf Adolfsson;Martin Alda;Lars Alfredsson;Lena Backlund;Bernhard T. Baune;Frank Bellivier;Susanne Bengesser;Wade H. Berrettini;Joanna M. Biernacka;Michael Boehnke;Anders D. Børglum;Gerome Breen;Vaughan J. Carr;Stanley Catts;Sven Cichon;Aiden Corvin;Nicholas Craddock;Udo Dannlowski;Dimitris Dikeos;Bruno Etain;Panagiotis Ferentinos;Mark Frye;Janice M. Fullerton;Micha Gawlik;Elliot S. Gershon;Fernando S. Goes;Melissa J. Green;Maria Grigoroiu-Serbanescu;Joanna Hauser;Frans A. Henskens;Jens Hjerling-Leffler;David M. Hougaard;Kristian Hveem;Nakao Iwata;Ian Jones;Lisa A. Jones;René S. Kahn;John R. Kelsoe;Tilo Kircher;George Kirov;Po-Hsiu Kuo;Mikael Landén;Marion Leboyer;Qingqin S. Li;Jolanta Lissowska;Christine Lochner;Carmel Loughland;Jurjen J. Luykx;Nicholas G. Martin;Carol A. Mathews;Fermin Mayoral;Susan L. McElroy;Andrew M. McIntosh;Francis J. McMahon;Sarah E. Medland;Ingrid Melle;Lili Milani;Philip B. Mitchell;Gunnar Morken;Ole Mors;Preben Bo Mortensen;Bertram Müller-Myhsok;Richard M. Myers;Woojae Myung;Benjamin M. Neale;Caroline M. Nievergelt;Merete Nordentoft;Markus M. Nöthen;John I. Nurnberger;Michael C. O’Donovan;Ketil J. Oedegaard;Tomas Olsson;Michael J. Owen;Sara A. Paciga;Christos Pantelis;Carlos N. Pato;Michele T. Pato;George P. Patrinos;Joanna M. Pawlak;Josep Antoni Ramos-Quiroga;Andreas Reif;Eva Z. Reininghaus;Marta Ribasés;Marcella Rietschel;Stephan Ripke;Guy A. Rouleau;Panos Roussos;Takeo Saito;Ulrich Schall;Martin Schalling;Peter R. Schofield;Thomas G. Schulze;Laura J. Scott;Rodney J. Scott;Alessandro Serretti;Jordan W. Smoller;Alessio Squassina

Writing - Review & Editing

;Eli A. Stahl;Hreinn Stefansson;Kari Stefansson;Eystein Stordal;Fabian Streit;Patrick F. Sullivan;Gustavo Turecki;Arne E. Vaaler;Eduard Vieta;John B. Vincent;Irwin D. Waldman;Cynthia S. Weickert;Thomas W. Weickert;Thomas Werge;David C. Whiteman;John-Anker Zwart;Howard J. Edenberg;Andrew McQuillin;Andreas J. Forstner;Niamh Mullins;Arianna Di Florio;Roel A. Ophoff;Ole A. Andreassen

2025-01-01

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Abstract

Bipolar disorder is a leading contributor to the global burden of disease(1). Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown(2). We analysed data from participants of European, East Asian, African American and Latino ancestries (n=158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings(3), and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder(4), highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.