O'Connell, Kevin S;
Koromina, Maria;
van der Veen, Tracey;
Boltz, Toni;
David, Friederike S;
Yang, Jessica Mei Kay;
Lin, Keng-Han;
... Bipolar Disorder Working Group of the Psychiatric Genomics Conso; + view all
(2025)
Genomics yields biological and phenotypic insights into bipolar disorder.
Nature
, 639
pp. 968-975.
10.1038/s41586-024-08468-9.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Genomics yields biological and phenotypic insights into bipolar disorder |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41586-024-08468-9 |
| Publisher version: | https://doi.org/10.1038/s41586-024-08468-9 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Bipolar disorder, Genetics of the nervous system, Genetics research, Genome-wide association studies |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry > Mental Health Neuroscience |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10206299 |
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