# Perspective Exploring Novel Associations of IL-18 Levels as a Mediator of the Causal Links between Major Depression and Reproductive Health

## TL;DR

This study explores how IL-18 levels might link depression and infertility, suggesting a genetic connection between mental health and reproductive health.

## Contribution

The novel contribution is identifying IL-18 as a mediator in the causal relationship between depression and female infertility using Mendelian randomization.

## Key findings

- Higher genetic risk for depression correlates with lower IL-18 levels.
- Genetically predicted IL-18 levels reduce the risk of female infertility.
- IL-18 partially mediates the effect of depression on certain types of female infertility.

## 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.