Mendelian Randomization Analysis Reveals Causal Associations Between Autoimmune Diseases and Female Infertility Risk

Jinyuan Wang; Haojun Long; Mingxuan Su; Yichang Cao; Runtang Zhou; Xiang Li; Jiangming Li; Yuxia Tang; Jiayi Tang; Simin Wang; Linyue Tang; Ruxin Chen; Danqi Deng; Li Tang

doi:10.1016/j.reprotox.2025.108984

Mendelian Randomization Analysis Reveals Causal Associations Between Autoimmune Diseases and Female Infertility Risk

Reprod Toxicol. 2025 Jul 2:108984. doi: 10.1016/j.reprotox.2025.108984. Online ahead of print.

Authors

Jinyuan Wang¹, Haojun Long², Mingxuan Su³, Yichang Cao³, Runtang Zhou³, Xiang Li³, Jiangming Li³, Yuxia Tang³, Jiayi Tang³, Simin Wang³, Linyue Tang³, Ruxin Chen⁴, Danqi Deng⁵, Li Tang⁶

Affiliations

¹ Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
² Department of Dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650101, China.
³ Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
⁴ Department of Gynecological Endocrinology, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, Jinan, 250001, China. Electronic address: crx0326@126.com.
⁵ Department of Dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650101, China. Electronic address: danqid128@sina.com.
⁶ Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China. Electronic address: tanglikm@163.com.

PMID: 40615097
DOI: 10.1016/j.reprotox.2025.108984

Abstract

Background: Infertility is viewed as a significant social challenge globally. Numerous observational studies have documented the link between autoimmune diseases (ADs) and female infertility, yet the underlying cause remained unclear. The primary objective of this study was to ascertain the causal connection between ADs and female infertility.

Method: We evaluated summary statistics from genome-wide association studies (GWAS) for prevalent autoimmune diseases (systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes (T1DM), celiac disease (CeD), inflammatory bowel disease (IBD), ankylosing spondylitis (AS), Crohn's disease (CD), ulcerative colitis (UC), psoriasis and female infertility. Initial two-sample Mendelian randomization (MR) analyses was conducted to pinpoint causal autoimmune diseases associated with female infertility in the discovery and replication analysis.

Results: Our two-sample Mendelian randomization analysis, using data from the UK Biobank and FinnGen (or IIBDGC), provided evidence for a causal association between genetically predicted rheumatoid arthritis (RA), type 1 diabetes (T1DM), celiac disease (CeD), and ulcerative colitis (UC) and an increased risk of female infertility. These associations were observed across different sub-phenotypes of infertility.

Conclusions: This Mendelian randomization study, based on large-scale GWAS datasets, provides genetic evidence supporting a causal association between several autoimmune diseases and increased female infertility risk. These findings highlight the potential role of immune-mediated mechanisms in reproductive dysfunction and may inform future research into early interventions and fertility-preserving strategies in affected individuals.

Keywords: Autoimmune disease; Female infertility; Rheumatoid arthritis; Two-sample Mendelian randomization; Type 1 diabetes.