Multivariate genome-wide association study dissects shared biology and disorder-specific loci across internalizing spectrum in millions of ancestrally diverse participants

ABSTRACT The extent of shared and disorder-specific etiology among generalized anxiety disorder (GAD), major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) remains unclear. Leveraging multiple cohorts, we conducted a multivariate and multi-ancestry genome-wide association study of GAD (N=1,358,762), MDD (N=3,601,629), and PTSD (N=1,617,876). We identified 248 loci associated with the latent internalizing disorder factor (INT), 591 with MDD, 237 with PTSD, and 109 with GAD. While GAD and PTSD genetic risk demonstrated strong overlap with the INT factor, 38% of MDD genetic signals were disorder-specific. Cross-population fine-mapping uncovered >450 causal variants, and the subsequent multi-omics characterization linked them to >1,250 genes, including both novel shared and disorder-specific loci. Considering the high-confidence findings converging across analytic approaches, we observed that the genetic liability shared across internalizing spectrum is driven by broadly acting cellular and regulatory mechanisms, whereas disorder-specific genetic risk reflects more specialized perturbations in neurodevelopmental, synaptic, and stress-responsive pathways.