Graduation Year

2026

Document Type

Thesis

Degree

M.S.P.H.

Degree Name

MS in Public Health (M.S.P.H.)

Degree Granting Department

Public Health

Major Professor

Monica Uddin, Ph.D.

Committee Member

Derek Wildman, Ph.D.

Committee Member

Chengqi Wang, Ph.D.

Keywords

cross-cohort analysis, depression, genetic ancestry, polygenic risk score performance, socioeconomic status

Abstract

Major Depressive Disorder (MDD) is a heterogeneous psychiatric condition influenced by genetic, sociodemographic, and environmental factors, yet the extent to which these factors jointly shape the timing of disease onset remains unclear. This study evaluated the effects of polygenic risk scores (PRS), sex, and socioeconomic status (SES) on age of onset for MDD across two independent cohorts: the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) (N = 486) and the All of Us Research Program (N = 8,014). Analyses were restricted to individuals of European genetic ancestry, and PRS were constructed using both European-ancestry (EA) and multi-ancestry (MA) genome-wide significant variants from a recent genome-wide association study (GWAS) meta-analysis. An SES composite index was made combining education, employment, and marital status. Linear regression models assessed associations between predictors and age of onset, and fully adjusted models incorporating PRS, sex, and SES were compared to single-predictor models using R2, Akaike Information Criterion (AIC), and Likelihood Ratio Tests (LRTs). Across both cohorts, higher PRS and female sex were associated with earlier age of onset, while SES demonstrated cohort-specific patterns. In PGRN-AMPS, higher SES was associated with later onset, whereas in All of Us, higher SES was associated with earlier onset, likely reflecting differences in cohort design and case identification. Fully adjusted models explained more variance in age of onset than models including individual predictors alone, indicating that genetic and sociodemographic factors contribute independently to onset timing. MA-derived PRS showed slightly stronger performance, as indicated by larger effect sizes, in both cohorts, although overall model fit was similar across PRS types and datasets. These findings highlight the importance of integrating genetic and sociodemographic information to better understand heterogeneity in MDD onset and the need to evaluate PRS performance and SES effects across diverse study populations.

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