Genomics yields biological and phenotypic insights into bipolar disorder
Journal
Nature
Journal Volume
639
Journal Issue
8056
Start Page
968
End Page
975
ISSN
0028-0836
Date Issued
2025-03-27
Author(s)
O'Connell, Kevin S
Koromina, Maria
van der Veen, Tracey
Boltz, Toni
David, Friederike S
Yang, Jessica Mei Kay
Lin, Keng-Han
Wang, Xin
Coleman, Jonathan R I
Mitchell, Brittany L
McGrouther, Caroline C
Rangan, Aaditya V
Lind, Penelope A
Koch, Elise
Harder, Arvid
Parker, Nadine
Bendl, Jaroslav
Adorjan, Kristina
Agerbo, Esben
Albani, Diego
Alemany, Silvia
Alliey-Rodriguez, Ney
Als, Thomas D
Andlauer, Till F M
Antoniou, Anastasia
Ask, Helga
Bass, Nicholas
Bauer, Michael
Beins, Eva C
Bigdeli, Tim B
Pedersen, Carsten Bøcker
Boks, Marco P
Børte, Sigrid
Bosch, Rosa
Brum, Murielle
Brumpton, Ben M
Brunkhorst-Kanaan, Nathalie
Budde, Monika
Bybjerg-Grauholm, Jonas
Byerley, William
Cabana-Domínguez, Judit
Cairns, Murray J
Carpiniello, Bernardo
Casas, Miquel
Cervantes, Pablo
Chatzinakos, Chris
Clarence, Tereza
Clarke, Toni-Kim
Claus, Isabelle
Coombes, Brandon
Corfield, Elizabeth C
Cruceanu, Cristiana
Cuellar-Barboza, Alfredo
Czerski, Piotr M
Dafnas, Konstantinos
Dale, Anders M
Dalkner, Nina
Degenhardt, Franziska
DePaulo, J Raymond
Djurovic, Srdjan
Drange, Ole Kristian
Escott-Price, Valentina
Fanous, Ayman H
Fellendorf, Frederike T
Ferrier, I Nicol
Forty, Liz
Frank, Josef
Frei, Oleksandr
Freimer, Nelson B
Fullard, John F
Garnham, Julie
Gizer, Ian R
Gordon, Scott D
Gordon-Smith, Katherine
Greenwood, Tiffany A
Grove, Jakob
Guzman-Parra, José
Ha, Tae Hyon
Hahn, Tim
Haraldsson, Magnus
Hautzinger, Martin
Havdahl, Alexandra
Heilbronner, Urs
Hellgren, Dennis
Herms, Stefan
Hickie, Ian B
Hoffmann, Per
Holmans, Peter A
Huang, Ming-Chyi
Ikeda, Masashi
Jamain, Stéphane
Johnson, Jessica S
Jonsson, Lina
Kalman, Janos L
Kamatani, Yoichiro
Kennedy, James L
Kim, Euitae
Kim, Jaeyoung
Kittel-Schneider, Sarah
Knowles, James A
Kogevinas, Manolis
Kranz, Thorsten M
Krebs, Kristi
Kushner, Steven A
Lavebratt, Catharina
Lawrence, Jacob
Leber, Markus
Lee, Heon-Jeong
Liao, Calwing
Lucae, Susanne
Lundberg, Martin
MacIntyre, Donald J
Maier, Wolfgang
Maihofer, Adam X
Malaspina, Dolores
Manchia, Mirko
Maratou, Eirini
Martinsson, Lina
Mattheisen, Manuel
McGregor, Nathaniel W
McInnis, Melvin G
McKay, James D
Medeiros, Helena
Meyer-Lindenberg, Andreas
Millischer, Vincent
Morris, Derek W
Moutsatsou, Paraskevi
Mühleisen, Thomas W
O'Donovan, Claire
Olsen, Catherine M
Panagiotaropoulou, Georgia
Papiol, Sergi
Pardiñas, Antonio F
Park, Hye Youn
Perry, Amy
Pfennig, Andrea
Pisanu, Claudia
Potash, James B
Quested, Digby
Rapaport, Mark H
Regeer, Eline J
Rice, John P
Rivera, Margarita
Schulte, Eva C
Senner, Fanny
Shadrin, Alexey
Shilling, Paul D
Sigurdsson, Engilbert
Sindermann, Lisa
Sirignano, Lea
Siskind, Dan
Slaney, Claire
Sloofman, Laura G
Smeland, Olav B
Smith, Daniel J
Sobell, Janet L
Soler Artigas, Maria
Stein, Dan J
Stein, Frederike
Su, Mei-Hsin
Sung, Heejong
Świątkowska, Beata
Terao, Chikashi
Tesfaye, Markos
Tesli, Martin
Thorgeirsson, Thorgeir E
Thorp, Jackson G
Toma, Claudio
Tondo, Leonardo
Tooney, Paul A
Tsai, Shih-Jen
Tsermpini, Evangelia Eirini
Vawter, Marquis P
Vedder, Helmut
Vreeker, Annabel
Walters, James T R
Winsvold, Bendik S
Witt, Stephanie H
Won, Hong-Hee
Ye, Robert
Young, Allan H
Zandi, Peter P
Zillich, Lea
Adolfsson, Rolf
Alda, Martin
Alfredsson, Lars
Backlund, Lena
Baune, Bernhard T
Bellivier, Frank
Bengesser, Susanne
Berrettini, Wade H
Biernacka, Joanna M
Boehnke, Michael
Børglum, Anders D
Breen, Gerome
Carr, Vaughan J
Catts, Stanley
Cichon, Sven
Corvin, Aiden
Craddock, Nicholas
Dannlowski, Udo
Dikeos, Dimitris
Etain, Bruno
Ferentinos, Panagiotis
Frye, Mark
Fullerton, Janice M
Gawlik, Micha
Gershon, Elliot S
Goes, Fernando S
Green, Melissa J
Grigoroiu-Serbanescu, Maria
Hauser, Joanna
Henskens, Frans A
Hjerling-Leffler, Jens
Hougaard, David M
Hveem, Kristian
Iwata, Nakao
Jones, Ian
Jones, Lisa A
Kahn, René S
Kelsoe, John R
Kircher, Tilo
Kirov, George
Landén, Mikael
Leboyer, Marion
Li, Qingqin S
Lissowska, Jolanta
Lochner, Christine
Loughland, Carmel
Luykx, Jurjen J
Martin, Nicholas G
Mathews, Carol A
Mayoral, Fermin
McElroy, Susan L
McIntosh, Andrew M
McMahon, Francis J
Medland, Sarah E
Melle, Ingrid
Milani, Lili
Mitchell, Philip B
Morken, Gunnar
Mors, Ole
Mortensen, Preben Bo
Müller-Myhsok, Bertram
Myers, Richard M
Myung, Woojae
Neale, Benjamin M
Nievergelt, Caroline M
Nordentoft, Merete
Nöthen, Markus M
Nurnberger, John I
O'Donovan, Michael C
Oedegaard, Ketil J
Olsson, Tomas
Owen, Michael J
Paciga, Sara A
Pantelis, Christos
Pato, Carlos N
Pato, Michele T
Patrinos, George P
Pawlak, Joanna M
Ramos-Quiroga, Josep Antoni
Reif, Andreas
Reininghaus, Eva Z
Ribasés, Marta
Rietschel, Marcella
Ripke, Stephan
Rouleau, Guy A
Roussos, Panos
Saito, Takeo
Schall, Ulrich
Schalling, Martin
Schofield, Peter R
Schulze, Thomas G
Scott, Laura J
Scott, Rodney J
Serretti, Alessandro
Smoller, Jordan W
Squassina, Alessio
Stahl, Eli A
Stefansson, Hreinn
Stefansson, Kari
Stordal, Eystein
Streit, Fabian
Sullivan, Patrick F
Turecki, Gustavo
Vaaler, Arne E
Vieta, Eduard
Vincent, John B
Waldman, Irwin D
Weickert, Cynthia S
Weickert, Thomas W
Werge, Thomas
Whiteman, David C
Zwart, John-Anker
Edenberg, Howard J
McQuillin, Andrew
Forstner, Andreas J
Mullins, Niamh
Di Florio, Arianna
Ophoff, Roel A
Andreassen, Ole A
Abstract
Bipolar disorder is a leading contributor to the global burden of disease. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown. 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, 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, 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.
Type
journal article