Mendelian Randomization Analysis on the Impacts of Age at Menarche on Adult Height: A Taiwanese Population Study

Backgrounds: Ample evidence supports potential influence of age at menarche (AM) on adult height (AH), but multiple confounders may affect causal estimates. To address this issue, the Mendelian randomization (MR) analysis was used to explore the causal impacts of AM on AH.

Methods: Using data (n = 57,349) from the publicly accessible Taiwan Biobank and randomly splitting them into 2 equal-size subsets, we identified single nucleotide polymorphisms (SNPs) significantly associated with AM in the exploration subset and used these SNPs as instrumental variables to estimate the effects of instruments on AH in the validation subset based on two stage least squares (2SLS) regression. In addition, three more summary statistics-based approaches, namely inverse variance weighted (IVW), MR-Egger, and weighted median (WM) analyses, were used to verify the findings. We also performed heterogeneity and sensitivity analyses to evaluate the robustness of the results.

Results: We identified 4 leading SNPs associated with AM at the genome-wide significant level, whereas rs9409082 may exert some pleiotropic effects on AH. After eliminating rs9409082, the 2SLS analysis indicated that one year delay in genetically determined AM predicted 1.5 cm height gain in adulthood (β = 1.508, 95% confidence interval [0.852, 2.163]). The causal relationship was also supported by WM (β = 1.183, [0.329, 2.038]) and IVW (β = 1.493, [0.523, 2.463]) methods.

Conclusions: Evidence from the present MR study supports a causal relationship between later AM and taller AH.