ABSTRACT Schizophrenia (SCZ) genetic liability, quantified by polygenic scores (PGS), may influence clinical phenotypes in major depressive disorder (MDD). We investigated the effect of the SCZ‐PGS derived from the latest SCZ genome‐wide association study (GWAS) on MDD symptom severity, comorbidities, and treatment outcomes. The study included 1060 adults diagnosed with MDD from the GSRD sample, with replication in the STAR*D sample ( n = 1503 MDD). Baseline and current depressive symptoms were assessed along with functional impairment and comorbid conditions. SCZ‐PGS was calculated based on the latest SCZ GWAS summary statistics. Higher SCZ‐PGS was associated with more severe baseline depressive symptoms, including apparent sadness, inner tension, lassitude, pessimistic thoughts, and suicidality. Functional impairment in social, familial, and work domains also increased with higher SCZ‐PGS. Multivariable models suggested a small but significant independent association between elevated SCZ‐PGS and poorer outcomes, confirmed in the STAR*D sample. Elevated SCZ‐PGS correlated with a series of features sugg
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