Scholarlink

Background <p>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.</p> Methods <p>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.</p> Results <p>GWAS revealed several loci with suggestive associations, including intronic variants in <i>SRCIN1</i> and <i>NKAIN3</i>, 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., <i>OLFM1</i>,<i> PTN</i>,<i> CACNB2</i>, <i>LHX6</i>). 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.</p> Conclusions <p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月28日

查看全文
  • Nan Lyu,
  • Qian Zhao,
  • Dannong Liu,
  • Jingjing Zhou,
  • Xuequan Zhu,
  • Han Qi,
  • Han Wang,
  • Min Liu,
  • Mengping Wei,
  • Chen Zhang,
  • Ling Zhang,
  • Jian Yang,
  • Gang Wang,
  • Mario Juruena,
  • Allan H Young

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.