Abstract P668: Age at Menarche, Adulthood Body Mass Index and Risk of Subclinical Atherosclerosis: A Mendelian Randomization Study

Abstract

Earlier age at menarche has been associated with an increased risk of cardiovascular diseases. It has been hypothesized that this association maybe mediated by higher body mass index which is in turn associated with earlier age at menarche. We performed a Mendelian randomization (MR) study to estimate the potential causal effect of age at menarche on carotid artery intima media thickness (cIMT; a marker of subclinical atherosclerosis), and the potential role of body mass index (BMI).Instrumental variables (IVs; P<5e-8) for age at menarche and BMI were obtained from ReproGen consortium (n=370,000 European women) and Neale Lab (n=194,174 European women), respectively. Genetic associations of the identified IVs with cIMT were obtained from our GWAS on cIMT among female participants in UKB. We used the inverse-variance weighted (IVW) method as the primary analysis and weighted median, MR-Egger, MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier), and MR-Lasso as sensitivity analyses. In addition, we used Steiger filtering to identify IVs that explain more variance in the exposure than the outcome.We found that an earlier age at menarche was associated with higher cIMT (β IVW =-0.01, P=0.002, 95%CI -0.016 to -0.004). After excluding invalid IVs identified using Steiger filtering and MR-PRESSO, this association was consistent using weighted median, MR-Egger, and MR-Lasso sensitivity methods. Similarly, an earlier age at menarche was also associated with lower adulthood BMI (β IVW =-0.109, P=3.15E-20, 95%CI -0.132 to -0.085). In the multi-variable MR (MVMR), age at menarche was not associated with cIMT after adjusting for adulthood BMI, but adulthood BMI was positively associated with cIMT after adjusting for AAM (β MVMR-IVW =0.02, P=0.004, 95%CI 0.005 to 0.027) suggesting that the effect of AAM on cIMT is partially mediated by adulthood BMI (% of mediation=21.8%).Our study suggests an earlier age at menarche as a potential causal risk factor for subclinical atherosclerosis. We also highlight that the effect of age at menarche on cIMT is potentially mediated by higher adulthood BMI.