Genomic dimensions deconstruct the clinical heterogeneity of bipolar disorder

Tracey van der Veen; Markos Tesfaye; Jessica Mei Kay Yang; Toni A. Boltz; Friederike Sophie David; Shane Crinion; Maria Koromina; Till F. M. Andlauer; Tim B. Bigdeli; Brandon J. Coombes; Tiffany A. Greenwood; Georgia Panagiotaropoulou; Nadine Parker; Heejong Sung; Nicholas James Bass; Jonathan R. I. Coleman; José Guzman-Parra; Janos L. Kalman; Caroline C. McGrouther; Brittany L. Mitchell; Aaditya V. Rangan; Katie Scott; Alexey A. Shadrin; Daniel J. Smith; Annabel Vreeker; Kristina Adorjan; Diego Albani; Silvia Alemany; Ney Alliey‐Rodriguez; Anastasia Antoniou

doi:10.1101/2025.06.23.25330155

Genetic & Genomic MedicinemedRxivJun 23, 2025

Preprint

Genomic dimensions deconstruct the clinical heterogeneity of bipolar disorder

Tracey van der Veen iD, Markos Tesfaye iD, Jessica Mei Kay Yang iD, Toni A. Boltz iD, Friederike Sophie David iD, Shane Crinion iD, Maria Koromina iD, Till F. M. Andlauer iD, Tim B. Bigdeli iD, Brandon J. Coombes iD, Tiffany A. Greenwood iD, Georgia Panagiotaropoulou iD, Nadine Parker iD, Heejong Sung iD, Nicholas James Bass iD, Jonathan R. I. Coleman iD, José Guzman-Parra iD, Janos L. Kalman iD, Caroline C. McGrouther, Brittany L. Mitchell iD, Aaditya V. Rangan iD, Katie Scott iD, Alexey A. Shadrin iD, Daniel J. Smith iD, Annabel Vreeker iD, , Melvin G. McInnis iD

Abstract

Bipolar disorders (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. BDs genetic architecture appears hierarchical--a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

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