Genome-wide association study of age at menarche in the Taiwan Biobank suggests NOL4 as a novel associated gene

Abstract

Sexual maturation is a complex physiological process that involves multiple variables, such as genetic and environmental factors. Among females, age at menarche (AM) is a critical milestone for sexual maturation. This study aimed to identify genetic markers of AM using nationwide population cohort data in Taiwan. Females with self-reported AM between 10 and 16 years (N = 39,827) were eligible for the final analysis. To identify genetic signals related to AM, we conducted a genome-wide association study using a linear regression model and split-half meta-analysis method to verify our findings. The Functional Mapping and Annotation web-based platform was used for positional mapping and gene-based and gene-set analyses. The meta-analysis identified four significant loci, i.e., LIN28B (pooled P = 1.39 × 10^-21), NOL4 (pooled P = 8.94 × 10^-9), GPR45 (pooled P = 4.19 × 10^-11), and LOC105373831 (pooled P = 4.37 × 10^-8), that were associated with AM. MAGMA gene-based analysis revealed that LIN28B (P = 1.13 × 10^-8), NOL4 (P = 2.27 × 10^-7), RXRG (P = 4.34 × 10-⁷), ETV5 (P = 1.75 × 10^-6), and HACE1 (P = 1.82 × 10^-6) were significantly associated with AM, while the gene-set analysis identified a significantly enriched pathway involving mTOR signaling complex (FDR corrected P = 1.28 × 10^-2). The results replicated evidence for several genetic markers associated with AM in the Taiwanese female population. Our analysis identified a novel locus (rs7239368) in NOL4 associated with AM (β = 0.051 ± 0.009 years, pooled P = 8.94 × 10^-9), whereas additional research is needed to validate its molecular role in sexual maturation.