Primary ovarian insufficiency consequence of autoimmune diseases: a bidirectional two-sample Mendelian randomization study

Abstract

Background: Observational studies suggest the risk of primary ovarian insufficiency (POI) is increased in autoimmune disorders (AIDs), but it is unclear whether there is a causal relationship. Therefore, we aimed to investigate the bidirectional causality between 20 AIDs and POI using Mendelian randomization (MR) analysis.

Methods: A bidirectional two-sample MR investigation was designed by using publicly accessible summary-level data from genome-wide association studies (GWAS). The inverse variance weighted (IVW) method was performed as the main analysis, supplemented by several sensitivity analyses. Cochran Q test was used to evaluate SNP estimate heterogeneity. MR-Egger and MR-PRESSO methods were utilized to detect horizontal pleiotropy.

Results: The MR analyses revealed that genetically determined coeliac disease (CeD) (OR = 1.124, 95% CI 1.033-1.224, P = 0.007), vitiligo (OR = 1.092, 95% CI 1.003-1.188; P = 0.042), systemic lupus erythematosus (SLE) (OR = 1.122, 95% CI 1.030-1.223, P = 0.008), and selective immunoglobulin A deficiency (SIgAD) (OR = 0.866, 95% CI: 0.776-0.967, P = 0.011) exhibited significant causal relationships with POI. We also found suggestive evidence of positive effect of Addison's disease (AD) towards POI (OR_5e-6 = 1.076, 95% CI 1.002-1.154, P = 0.043).

Conclusion: This comprehensive MR analysis indicated that SLE, CeD, vitiligo, and AD caused an increased risk of POI, SIgAD was associated with a decreased risk of POI. These insights carry profound clinical implications, particularly emphasizing the early intervention for women with AIDs/POI who wish to preserve their reproductive potential or plan for future pregnancies.

Keywords: Mendelian randomization; autoimmune disease; causal association; primary ovarian insufficiency; single-nucleotide polymorphisms.

Figure 1

Overview of the bidirectional two-sample MR analysis. Assumption 1: genetic instrumental variables are strongly related to the exposure; Assumption 2: genetic instrumental variables are independent from confounding factors of the exposure-outcome; Assumption 3: genetic instrumental variables influence outcomes solely through the exposure. SNPs, single nucleotide polymorphisms; POI, primary ovarian insufficiency; LD, linkage disequilibrium.

Figure 2

Forest plot illustrating the causal effect of autoimmune diseases on primary ovarian insufficiency. The causal effect of different autoimmune diseases on primary ovarian insufficiency was expressed as OR per unit. Error bars represent the 95% CIs of the estimates. GI, gastrointestinal; SNPs, single nucleotide polymorphisms; OR, odds ratio; CI, confidence interval.

Figure 3

Forest plot illustrating the associations of the genetically predicted primary ovarian insufficiency with the risk of autoimmune diseases. The causal effect of primary ovarian insufficiency on different autoimmune diseases was expressed as OR per unit. Error bars represent the 95% CIs of the estimates. GI, gastrointestinal; OR, odds ratio; CI, confidence interval.