Genomics yields biological and phenotypic insights into bipolar disorder

Abstract Bipolar disorder (BD) 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 BD cases, 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 4-fold increase over previous findings 3 , and identified a novel 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 BD. Genes prioritised through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in BD cases 4 , highlighting convergence of common and rare variant signals. We report differences in genetic architecture of BD depending on the source of patient ascertainment and on BD-subtype (BDI and BDII). Several analyses implicate specific cell types in BD pathophysiology, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide novel insights into the genetic architecture and biological underpinnings of BD.