Citations 1
Genomic dimensions deconstruct the clinical heterogeneity of bipolar disorder
Veen, Tracey van der , Tesfaye, Markos , Yang, Jessica , Boltz, Toni , David, Friederike S. , Crinion, Shane , Koromina, Maria , Bigdeli, Tim B., Coombes, Brandon J., Panagiotaropoulou, Georgia, Parker, Nadine, Sung, Heejong , Bass, Nicholas, Coleman, Jonathan R. I., Guzman-Parra, José , Kálmán, János , McGrouther, Caroline C., Rangan, Aaditya V. , Scott, Katie , Vreeker, Annabel , Bauer, Michael , Brunkhorst-Kanaan, Nathalie, Byerley, William , Cervantes, Pablo , Chatzinakos, Chris , Claus, Isabelle , Cruceanu, Cristiana , Cuellar-Barboza, Alfredo, Dafnas, Konstantinos , Degenhardt, Franziska, Fanous, Ayman H. , Ferrier, I. 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No container title available | June 25, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
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 diagnostic subtypes.