Scholarlink

<p>Major Depressive Disorder (MDD) is a prevalent, chronic, and debilitating psychiatric illness that contributes substantially to global disability and disease burden. Dysregulation of the canonical Wnt/β-catenin and G-protein signaling architectures has been strongly implicated in this molecular etiology because of their crucial roles in synaptic plasticity and stress resilience. However, individual genetic association studies focusing on distinct variants within these pathways have yielded largely inconsistent results. To address these discrepancies, this study provides a systematic review and meta-analysis quantitatively synthesizing data from 8 independent case-control datasets published through 2025 targeting the most frequently investigated polymorphisms: <i>GSK3B</i> (rs334558, rs6438552) and <i>GNB3</i> (rs5443). Pooled Odds Ratios (ORs) and 95% Confidence Intervals (CIs) were evaluated using a random-effects framework, defining the allele contrast as the primary outcome to control for multiple testing. For <i>GSK3B</i> rs334558, the pooled analysis demonstrated a significant protective association against MDD risk under the allele contrast model (T vs C: OR = 0.80; 95 % CI: 0.68 – 0.93; p &lt; 0.01), with consistent protective trends replicated in recessive and homozygous contrasts. Similarly, the <i>GSK3B</i> rs6438552 variant exhibited a protective trend (G vs A: OR = 0.72; 95 % CI: 0.59 – 0.89), which was most pronounced in the homozygous mutant contrast (GG vs AA: OR = 0.57; 95 % CI: 0.42 – 0.78). Ancestry-stratified subgroup analyses revealed that these protective effects were primarily localized within East Asian cohorts. Conversely, the synthesis of <i>GNB3</i> rs5443 yielded evidence of a highly heterogeneous, context-dependent relationship (I<sup>2</sup> = 89% in the overdominant model). While fixed-effect modeling indicated a localized risk association within European and Korean subgroups under a recessive framework (OR = 1.62; 95% CI: 1.05 – 2.52), publication bias assessments suggested that these specific subgroup risks may be numerically inflated due to an underreporting of small-scale null findings. Taken together, our findings indicate that specific <i>GSK3B</i> variants may confer innate molecular resilience against MDD by modulating downstream Wnt signaling integrity, whereas the <i>GNB3</i> rs5443 polymorphism operates as an ethnicity-dependent genetic modifier rather than a universal susceptibility factor. These exploratory insights highlight key pathways requiring large-scale genomic validation to confirm their future clinical utility in precision psychiatry stratification.</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

Association of specific GSK3β (rs334558, rs6438552) and GNB3 (rs5443) polymorphisms with major depressive disorder: a meta-analysis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月15日

查看全文
  • Yuvapriya Kalidasan,
  • Suvarna Jyothi Kantipudi,
  • Ilangovan Ramachandran,
  • Vettriselvi Venkatesan

摘要

Major Depressive Disorder (MDD) is a prevalent, chronic, and debilitating psychiatric illness that contributes substantially to global disability and disease burden. Dysregulation of the canonical Wnt/β-catenin and G-protein signaling architectures has been strongly implicated in this molecular etiology because of their crucial roles in synaptic plasticity and stress resilience. However, individual genetic association studies focusing on distinct variants within these pathways have yielded largely inconsistent results. To address these discrepancies, this study provides a systematic review and meta-analysis quantitatively synthesizing data from 8 independent case-control datasets published through 2025 targeting the most frequently investigated polymorphisms: GSK3B (rs334558, rs6438552) and GNB3 (rs5443). Pooled Odds Ratios (ORs) and 95% Confidence Intervals (CIs) were evaluated using a random-effects framework, defining the allele contrast as the primary outcome to control for multiple testing. For GSK3B rs334558, the pooled analysis demonstrated a significant protective association against MDD risk under the allele contrast model (T vs C: OR = 0.80; 95 % CI: 0.68 – 0.93; p < 0.01), with consistent protective trends replicated in recessive and homozygous contrasts. Similarly, the GSK3B rs6438552 variant exhibited a protective trend (G vs A: OR = 0.72; 95 % CI: 0.59 – 0.89), which was most pronounced in the homozygous mutant contrast (GG vs AA: OR = 0.57; 95 % CI: 0.42 – 0.78). Ancestry-stratified subgroup analyses revealed that these protective effects were primarily localized within East Asian cohorts. Conversely, the synthesis of GNB3 rs5443 yielded evidence of a highly heterogeneous, context-dependent relationship (I2 = 89% in the overdominant model). While fixed-effect modeling indicated a localized risk association within European and Korean subgroups under a recessive framework (OR = 1.62; 95% CI: 1.05 – 2.52), publication bias assessments suggested that these specific subgroup risks may be numerically inflated due to an underreporting of small-scale null findings. Taken together, our findings indicate that specific GSK3B variants may confer innate molecular resilience against MDD by modulating downstream Wnt signaling integrity, whereas the GNB3 rs5443 polymorphism operates as an ethnicity-dependent genetic modifier rather than a universal susceptibility factor. These exploratory insights highlight key pathways requiring large-scale genomic validation to confirm their future clinical utility in precision psychiatry stratification.