Am J Med Genet B Neuropsychiatr Genet. 2025 Oct 20. doi: 10.1002/ajmg.b.33066. Online ahead of print.
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 suggesting more severe depression in both samples. Our findings confirm that the latest SCZ genetic liability scores contribute to MDD clinical heterogeneity, increasing depressive severity, functional impairment, and anxiety comorbidity. Although its influence on treatment response appears modest, SCZ-PGS may serve as a marker for more severe depressive presentations.
PMID:41115750 | DOI:10.1002/ajmg.b.33066
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