Abstract
This research has suggested a link between major depressive disorder (MDD) and infertility, with interleukin‐18 (IL‐18) being proposed as a potential mediator due to its connections to both conditions. A Mendelian randomization (MR) approach was utilized in this study, which drew on genetic data from 500,199 European participants studied for MDD, along with additional IL‐18 and reproductive health data from the FinnGen consortium and GWAS datasets. Single nucleotide polymorphisms were employed as instrumental variables to examine the causal relationships between MDD, genetically predicted IL‐18 levels, and infertility. In our study, bidirectional MR analysis revealed a significant inverse causal relationship between MDD and genetically predicted IL‐18 levels, with a higher genetic predisposition to MDD, correlating with reduced IL‐18 levels (β: −0.40; 95% confidence interval (CI): −0.69 to −0.11; P = 7.09 × 10−3). Additionally, MDD is found to significantly increase the risk of female infertility. Notably, genetically predicted IL‐18 levels demonstrated a protective effect against female infertility (odds ratio (OR): 0.92; 95% CI: 0.86–0.98; P = 1.17 × 10−2). Mediation analysis indicated that genetically predicted IL‐18 levels partially mediated the impact of MDD on female infertility associated with cervical, vaginal, other or unspecified origin, accounting for up to 14.61% of this effect. No evidence of pleiotropy or heterogeneity was detected. The role of genetic predispositions to MDD in influencing genetically predicted IL‐18 levels, and subsequently, female infertility, was highlighted by our study, offering insights into the complex interplay between mental health and reproductive biology. These findings contribute to a deeper understanding of the genetic and molecular pathways influencing these conditions, suggesting new directions for research and potential therapeutic interventions.