Year: 2026
Type: preprint
Abstract: Bipolar disorder's (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD's genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity, beyond subtypes.
Source: Research Square
Author: Tracey van der Veen
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1092932281, G2129077002, 1/7 Psychiatric Genomics Consortium: Finding actionable variation, 1/5-The Psychiatric GWAS Consortium: Integrated & Coordinated GWAS Meta-Analyses, 1/4 Psychiatric GWAS Consortium: Genomic Follow-up Next-Gen Seq & Genotyping, G5928719961, G596731591, 3/7 Psychiatric Genomics Consortium: Advancing Discovery and Impact
OpenAlex ID: W7204259196