Genetic Relationship Between Menarche and Height in East Asians: Functional Role of LIN28B in Pubertal Timing and...

Observational and genetic studies associate later menarche with greater height, but their causal relationship, shared genomic regions, and LIN28B's role in puberty and growth remain unclear.

We conducted genetic correlation, bidirectional Mendelian randomization (MR), and local genetic correlation analyses between menarche timing and adult height in 309,507 East Asians from Taiwan Biobank (TWB), Biobank Japan (BBJ), and the Korean Genome and Epidemiology Study (KoGES). We also examined how LIN28B overexpression affects chondrocyte maturation and hypothalamic-pituitary-gonadal (HPG) axis activation.

Later menarche showed a positive genetic correlation with taller stature in both BBJ (Rg = 0.200, p = 1.82 × 10^-8) and KoGES (Rg = 0.211, p = 7.62 × 10^-8) datasets. MR confirmed a bidirectional causal relationship, indicating that later menarche increased height (MR-weighted median: β = 0.103, p = 4.32 × 10^-9), whereas taller stature delayed menarche (MR-PRESSO [outlier-corrected]: β = 0.174, p = 1.26 × 10^-3). Local genetic correlation analysis revealed five genomic regions with significant positive associations (p < 0.05/1664), including a critical locus on chromosome six harboring LIN28B, suggesting its important role in both traits. In vitro, LIN28B overexpression enhanced chondrocyte proliferation while inhibiting their differentiation and suppressed hypothalamic GnRH expression (p < 0.05), suggesting its dual regulation of growth and puberty.

Our findings demonstrate a bidirectional relationship between menarche timing and adult height in East Asians, highlight five shared genomic regions, and underscore LIN28B's role in hormonal and chondrocyte activity as a potential regulator of pubertal timing and growth.