Genome-wide association and DNA methylation analyses of SSRI treatment response in major depressive disorder

Selective serotonin reuptake inhibitors (SSRIs) are first-line treatments for major depressive disorder (MDD); however, patient responses vary significantly. This study explored genetic and epigenetic factors linked to SSRI response to better understand this heterogeneity. We performed a genome-wide association study (GWAS) in 852 MDD patients classified as SSRI responders or non-responders. A polygenic risk score (PRS) analysis was conducted to estimate the cumulative effect of common genetic variants. In a subset of 66 participants, genome-wide DNA methylation profiling was carried out using the Illumina Methylation EPIC array. Analyses included the identification of differentially methylated positions (DMPs) and regions (DMRs), as well as weighted gene co-methylation network analysis (WGCNA) and downstream pathway and protein–protein interaction (PPI) analyses. GWAS revealed several loci with suggestive associations, including intronic variants in SRCIN1 and NKAIN3, although none reached genome-wide significance. The PRS explained a small proportion of variance in SSRI response and did not yield statistically significant results. DNA methylation analysis identified nominally differentially methylated CpGs in genes involved in synaptic signaling and neurodevelopment (e.g., OLFM1, PTN, CACNB2, LHX6). In addition, WGCNA identified a co-methylation module that showed a trend-level association with SSRI response after adjustment for clinical covariates, and hub genes within this module were functionally linked to neuronal signaling in PPI network analysis. Although no single marker reached significance, the results suggest that synaptic plasticity and neurodevelopment may influence SSRI response. These genomic and epigenomic insights offer molecular clues that may inform future studies on the biological mechanisms underlying antidepressant response.