TY - JOUR
T1 - Genomics yields biological and phenotypic insights into bipolar disorder
AU - O'Connell, Kevin S
AU - Koromina, Maria
AU - van der Veen, Tracey
AU - Boltz, Toni
AU - David, Friederike S
AU - Yang, Jessica Mei Kay
AU - Lin, Keng-Han
AU - Wang, Xin
AU - Coleman, Jonathan R I
AU - Mitchell, Brittany L
AU - McGrouther, Caroline C
AU - Rangan, Aaditya V
AU - Lind, Penelope A
AU - Koch, Elise
AU - Harder, Arvid
AU - Parker, Nadine
AU - Bendl, Jaroslav
AU - Adorjan, Kristina
AU - Agerbo, Esben
AU - Albani, Diego
AU - Alemany, Silvia
AU - Alliey-Rodriguez, Ney
AU - Als, Thomas D
AU - Andlauer, Till F M
AU - Antoniou, Anastasia
AU - Ask, Helga
AU - Bass, Nicholas
AU - Bauer, Michael
AU - Beins, Eva C
AU - Bigdeli, Tim B
AU - Pedersen, Carsten Bøcker
AU - Boks, Marco P
AU - Børte, Sigrid
AU - Bosch, Rosa
AU - Brum, Murielle
AU - Brumpton, Ben M
AU - Brunkhorst-Kanaan, Nathalie
AU - Budde, Monika
AU - Bybjerg-Grauholm, Jonas
AU - Byerley, William
AU - Cabana-Domínguez, Judit
AU - Cairns, Murray J
AU - Carpiniello, Bernardo
AU - Casas, Miquel
AU - Grove, Jakob
AU - Mattheisen, Manuel
AU - Stein, Dan J
AU - Børglum, Anders D
AU - Mors, Ole
AU - Mortensen, Preben Bo
AU - 23andMe Research Team
N1 - © 2025. The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2025/1/22
Y1 - 2025/1/22
N2 - 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.
AB - 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.
U2 - 10.1038/s41586-024-08468-9
DO - 10.1038/s41586-024-08468-9
M3 - Journal article
C2 - 39843750
SN - 0028-0836
JO - Nature
JF - Nature
ER -