Schizophrenia Genetics Modulates Clinical Depressive Features

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.

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Publication Details

Journal
American Journal of Medical Genetics Part B Neuropsychiatric Genetics
Published
2025-10-20
DOI
https://doi.org/10.1002/ajmg.b.33066
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
0.00

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article

Schizophrenia Genetics Modulates Clinical Depressive Features

Stuart Montgomery, Joseph Zohar, Raffaele Ferri, Panagiotis P. Ferentinos et al.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics
Genetic Associations and Epidemiology
article

Schizophrenia Genetics Modulates Clinical Depressive Features

Stuart Montgomery, Joseph Zohar, Raffaele Ferri, Panagiotis P. Ferentinos, Julien Mendlewicz, Raffaella Zanardi, Giuseppe Fanelli, Chiara Fabbri, Francesco Benedetti, Dan Rujescu, Daniel Souery, Alessandro Serretti, Siegfried Kasper, Bernhard T. Baune
article en

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.

American Journal of Medical Genetics Part B Neuropsychiatric GeneticsVol. 201(3)
Université Libre de Bruxelles (BE), Radboud University Nijmegen (NL), Vita-Salute San Raffaele University (IT), Tel Aviv University (IL), The University of Melbourne (AU), University of Münster (DE), Florey Institute of Neuroscience and Mental Health (AU), Università degli Studi di Enna Kore (IT), Sheba Medical Center (IL), Radboud University Medical Center (NL), Oasi Maria SS (IT), Neuroscience Institute (IT), IRCCS Ospedale San Raffaele (IT), Athens Medical Center (GR), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), Imperial College London (GB), Athens State University (US), Medical University of Vienna (AT), University of Bologna (IT)
European Commission, HORIZON EUROPE Framework Programme, National Institute of Mental Health
Openalex Percentile: Top 68%
Genetic Associations and Epidemiology
DOIOpen Access PDFOpenAlex
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