Genomic discoveries in bipolar disorder inform biology and clinical outcomes: an update

Bipolar disorder has a high heritability. Still, most of the molecular genetics factors are mainly unknown. The recent multi-ancestry genome-wide study of 158,036 cases and 2,796,499 controls from the Psychiatric Genomics Consortium identified 298 genomic loci [1]. Follow-up analyses revealed convergence of common and rare genetic variants and implicated 36 credible genes. Further, we found enrichment of GABAergic interneurons and medium spiny neurons. The genetic architecture depended on patient ascertainment and subtype (I or II). Separate analysis for clinical, community and self-reported samples identified differences in the underlying genetics of bipolar disorder depending on the source of patient ascertainment and on subtype. Most psychiatric disorders were more strongly correlated with the full meta-analysis, bipolar disorder type II, and bipolar disorder in community and self-reported samples. In contrast, schizophrenia was more strongly genetically correlated with the full bipolar disorder dataset (excluding self-reported data) and with bipolar disorder type 1 and bipolar disorder in clinical samples . Our analyses revealed novel neurobiological insights and suggested several potential avenues for new pharmacological targets, and shows a different genetic architecture across the bipolar spectrum. Further, recent analyses also suggest that genomic information can be used for stratification and outcome prediction, but these tools are still uncertain.

[1] O’Connell, K. S. et al. Genomics yields biological and phenotypic insights into bipolar disorder. Nature 639, 968–975 (2025).