Epidemiologic and genetic associations of female reproductive disorders with depression or dysthymia: a Mendelian randomization study

Abstract

Observational studies have previously reported an association between depression and certain female reproductive disorders. However, the causal relationships between depression and different types of female reproductive disorders remain unclear in terms of direction and magnitude. We conducted a comprehensive investigation using a two-sample bi-directional Mendelian randomization analysis, incorporating publicly available GWAS summary statistics. Our aim was to establish a causal relationship between genetically predicted depression and the risk of various female reproductive pathological conditions, such as ovarian dysfunction, polycystic ovary syndrome(PCOS), ovarian cysts, abnormal uterine and vaginal bleeding(AUB), endometriosis, leiomyoma of the uterus, female infertility, spontaneous abortion, eclampsia, pregnancy hypertension, gestational diabetes, excessive vomiting in pregnancy, cervical cancer, and uterine/endometrial cancer. We analyzed a substantial sample size, ranging from 111,831 to 210,870 individuals, and employed robust statistical methods, including inverse variance weighted, MR-Egger, weighted median, and MR-PRESSO, to estimate causal effects. Sensitivity analyses, such as Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots, were also conducted to ensure the validity of our results. Furthermore, risk factor analyses were performed to investigate potential mediators associated with these observed relationships. Our results demonstrated that genetic predisposition to depression or dysthymia was associated with an increased risk of developing PCOS (OR = 1.43, 95% CI 1.28-1.59; P = 6.66 × 10^-11), ovarian cysts (OR = 1.36, 95% CI 1.20-1.55; P = 1.57 × 10^-6), AUB (OR = 1.41, 95% CI 1.20-1.66; P = 3.01 × 10^-5), and endometriosis (OR = 1.43, 95% CI 1.27-1.70; P = 2.21 × 10^-7) after Bonferroni correction, but no evidence for reverse causality. Our study did not find any evidence supporting a causal or reverse causal relationship between depression/dysthymia and other types of female reproductive disorders. In summary, our study provides evidence for a causal relationship between genetically predicted depression and specific types of female reproductive disorders. Our findings emphasize the importance of depression management in the prevention and treatment of female reproductive disorders, notably including PCOS, ovarian cysts, AUB, and endometriosis.

Keywords: Causality; Depression or dysthymia; Female reproductive disorders; GWAS; Mendelian randomization.

Figure 1

Causal effects for depression or dysthymia on ovarian and uterine-related disorders. Summary of the Mendelian randomization (MR) estimates derived from the inverse-variance weighted (IVW), MR-Egger, weighted median (WM) and MR-PRESSO methods.

Figure 2

Causal effects for depression or dysthymia on fertility and pregnancy-related disorders.

Figure 3

Causal effects for depression or dysthymia on reproductive-related cancers.

Figure 4

Scatter plots depicting the impact of genetically predicted depression/dysthymia on the risk of female reproductive disorders.

Figure 5

Funnel plots depicting the impact of genetically predicted depression or dysthymia on the risk of female reproductive disorders. The funnel plots show the Inverse variance weighted and MR-Egger MR estimate of each depression/dysthymia single-nucleotide polymorphism with different female reproductive disorders versus 1/standard error (1/SE_IV). (a) PCOS; (b) ovarian cysts; (c) AUB; (d) endometriosis; (e) leiomyoma of the uterus; (f) gestational diabetes.