The Causal Effect of Adult Height on Late-Life Handgrip Strength: The Singapore Chinese Health Study

Abstract Background Adult height has been associated with handgrip strength, which is a surrogate marker of physical frailty. However, it is uncertain if this association is causative or due to confounding bias. Methods We evaluated pairwise associations among handgrip strength, adult height, and genetically determined height (using a polygenic score [PGS] for height in a mediation framework and a 2-sample Mendelian randomization approach) by means of a multivariable regression model using a prospective cohort of Chinese living in Singapore. We additionally evaluated pathway enrichments of height-related genes in relation to increased handgrip strength to discover common biological mechanisms underlying associations of genetically determined height with handgrip strength. Results Height PGS exhibited a positive association with handgrip strength at late life after adjusting for midlife body weight and other baseline exposures (cigarette smoking, education, and physical activity status, p = 1.2 × 10−9). Approximately 66.4% of the total effect of height PGS on handgrip strength was mediated through adult height (βindirect-effect = 0.034, pindirect-effect = 1.4 × 10−40). Two-sample Mendelian randomization evaluations showed a consistent causal relationship between increased height and increased handgrip strength in late life (p between 6.6 × 10−4 and 3.9 × 10−18), with insignificant horizontal pleiotropic effects (pMR-Egger intercept = 0.853). Pathway analyses of genes related to both increased adult height and handgrip strength revealed enrichment in ossification and adipogenesis pathways (padj between .034 and 6.8 × 10−4). Conclusions The study highlights a potentially causal effect between increased adult height and increased handgrip strength in late life, which may be explained by related biological processes underlying the preservation of muscle mass and strength in aging.