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Lookup NU author(s): Emeritus Professor Nicol Ferrier
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© The Author(s), under exclusive licence to Springer Nature Limited 2025. Bipolar disorder is a leading contributor to the global burden of disease1. Despite high heritability (60–80%), the majority of the underlying genetic determinants remain unknown2. 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 findings3, 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 disorder4, 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.
Author(s): O'Connell KS, Koromina M, van der Veen T, Boltz T, David FS, Yang JMK, Lin K-H, Wang X, Coleman JRI, Mitchell BL, McGrouther CC, Rangan AV, Lind PA, Koch E, Harder A, Parker N, Bendl J, Adorjan K, Agerbo E, Albani D, Alemany S, Alliey-Rodriguez N, Als TD, Andlauer TFM, Antoniou A, Ask H, Bass N, Bauer M, Beins EC, Bigdeli TB, Pedersen CB, Boks MP, Borte S, Bosch R, Brum M, Brumpton BM, Brunkhorst-Kanaan N, Budde M, Bybjerg-Grauholm J, Byerley W, Cabana-Dominguez J, Cairns MJ, Carpiniello B, Casas M, Cervantes P, Chatzinakos C, Chen H-C, Clarence T, Clarke T-K, Claus I, Coombes B, Corfield EC, Cruceanu C, Cuellar-Barboza A, Czerski PM, Dafnas K, Dale AM, Dalkner N, Degenhardt F, DePaulo JR, Djurovic S, Drange OK, Escott-Price V, Fanous AH, Fellendorf FT, Ferrier IN, Forty L, Frank J, Frei O, Freimer NB, Fullard JF, Garnham J, Gizer IR, Gordon SD, Gordon-Smith K, Greenwood TA, Grove J, Guzman-Parra J, Ha TH, Hahn T, Haraldsson M, Hautzinger M, Havdahl A, Heilbronner U, Hellgren D, Herms S, Hickie IB, Hoffmann P, Holmans PA, Huang M-C, Ikeda M, Jamain S, Johnson JS, Jonsson L, Kalman JL, Kamatani Y, Kennedy JL, Kim E, Kim J, Kittel-Schneider S, Knowles JA, Kogevinas M, Kranz TM, Krebs K, Kushner SA, Lavebratt C, Lawrence J, Leber M, Lee H-J, Liao C, Lucae S, Lundberg M, MacIntyre DJ, Maier W, Maihofer AX, Malaspina D, Manchia M, Maratou E, Martinsson L, Mattheisen M, McGregor NW, McInnis MG, McKay JD, Medeiros H, Meyer-Lindenberg A, Millischer V, Morris DW, Moutsatsou P, Muhleisen TW, O'Donovan C, Olsen CM, Panagiotaropoulou G, Papiol S, Pardinas AF, Park HY, Perry A, Pfennig A, Pisanu C, Potash JB, Quested D, Rapaport MH, Regeer EJ, Rice JP, Rivera M, Schulte EC, Senner F, Shadrin A, Shilling PD, Sigurdsson E, Sindermann L, Sirignano L, Siskind D, Slaney C, Sloofman LG, Smeland OB, Smith DJ, Sobell JL, Soler Artigas M, Stein DJ, Stein F, Su M-H, Sung H, Swiatkowska B, Terao C, Tesfaye M, Tesli M, Thorgeirsson TE, Thorp JG, Toma C, Tondo L, Tooney PA, Tsai S-J, Tsermpini EE, Vawter MP, Vedder H, Vreeker A, Walters JTR, Winsvold BS, Witt SH, Won H-H, Ye R, Young AH, Zandi PP, Zillich L, Huang GD, Harvey PD, Aslan M, Kim DJ, Cheon MJ, Kang JH, Lee YK, Kim J-W, Lee B-C, Adolfsson R, Alda M, Alfredsson L, Backlund L, Baune BT, Bellivier F, Bengesser S, Berrettini WH, Biernacka JM, Boehnke M, Borglum AD, Breen G, Carr VJ, Catts S, Cichon S, Corvin A, Craddock N, Dannlowski U, Dikeos D, Etain B, Ferentinos P, Frye M, Fullerton JM, Gawlik M, Gershon ES, Goes FS, Green MJ, Grigoroiu-Serbanescu M, Hauser J, Henskens FA, Hjerling-Leffler J, Hougaard DM, Hveem K, Iwata N, Jones I, Jones LA, Kahn RS, Kelsoe JR, Kircher T, Kirov G, Kuo P-H, Landen M, Leboyer M, Li QS, Lissowska J, Lochner C, Loughland C, Luykx JJ, Martin NG, Mathews CA, Mayoral F, McElroy SL, McIntosh AM, McMahon FJ, Medland SE, Melle I, Milani L, Mitchell PB, Morken G, Mors O, Mortensen PB, Muller-Myhsok B, Myers RM, Myung W, Neale BM, Nievergelt CM, Nordentoft M, Nothen MM, Nurnberger JI, O'Donovan MC, Oedegaard KJ, Olsson T, Owen MJ, Paciga SA, Pantelis C, Pato CN, Pato MT, Patrinos GP, Pawlak JM, Ramos-Quiroga JA, Reif A, Reininghaus EZ, Ribases M, Rietschel M, Ripke S, Rouleau GA, Roussos P, Saito T, Schall U, Schalling M, Schofield PR, Schulze TG, Scott LJ, Scott RJ, Serretti A, Smoller JW, Squassina A, Stahl EA, Stefansson H, Stefansson K, Stordal E, Streit F, Sullivan PF, Turecki G, Vaaler AE, Vieta E, Vincent JB, Waldman ID, Weickert CS, Weickert TW, Werge T, Whiteman DC, Zwart J-A, Edenberg HJ, McQuillin A, Forstner AJ, Mullins N, Di Florio A, Ophoff RA, Andreassen OA
Publication type: Article
Publication status: Published
Journal: Nature
Year: 2025
Volume: 639
Pages: 968-975
Print publication date: 27/03/2025
Online publication date: 22/01/2025
Acceptance date: 28/11/2024
ISSN (print): 0028-0836
ISSN (electronic): 1476-4687
Publisher: Nature Research
URL: https://doi.org/10.1038/s41586-024-08468-9
DOI: 10.1038/s41586-024-08468-9
PubMed id: 39843750
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