Using genetic instruments to estimate the causal effect of hormonal reproductive factors on osteoarthritis

OBJECTIVES: Hormonal reproductive factors have been considered to play an important role in the etiology of osteoarthritis (OA). We performed Mendelian randomization (MR) to examine whether a causal effect existed between them. METHODS: MR was performed by using publicly released genome-wide association study (GWAS) summary statistics to estimate the causal associations of three relevant exposures, including age at menarche (AAM), age at natural menopause (ANM) and age at first birth (AFB), with the risk of OA. We employed several MR methods, including inverse-variance weighted (IVW), MR-Egger regression, weighted median and weighted mode, to estimate the causality. We performed a sensitivity analysis by manually pruning pleiotropic variants associated with the known confounder body mass index (BMI). RESULTS: The instrumental variables that achieved genome-wide significance, including 349 AAM single nucleotide polymorphisms (SNPs), 121 AAM SNPs, 54 ANM SNPs, and 10 AFB SNPs, were incorporated into the operation. IVW analysis indicated that each additional year in AFB was associated with a decreasing risk of hip and/or knee OA and overall OA (hip and/or knee OA: OR = 0.79, 95% CI: 0.64–0.93, P = 1.33 × 10(−3); overall OA: OR = 0.80, 95% CI: 0.68–0.92, P = 1.80 × 10(−4)). In addition, our results suggested that AAM exerted a causal effect on knee OA in an unfavorable manner (OR = 0.86, 95% CI: 0.76–0.95, P = 1.58 × 10(−3)). After accounting for the effect of BMI, the causal effect association between AFB and hip and/or knee OA was also examined (IVW: OR = 0.78, 95% CI: 0.66–0.92, P = 3.22 × 10(−3)). CONCLUSION: Our findings add a growing body of evidence surrounding the unfavorable effects of early AFB on OA risk, suggesting the essential for relevant health problem management in susceptible populations.