Genome-wide association and integrative analyses of relative handgrip strength identify polygenic determinants of gastrointestinal disorder susceptibility

BACKGROUND: Hand grip strength is a crucial indicator of muscle strength and quality. Yet, there remain significant knowledge gaps in our understanding of the genetic factors that influence hand grip strength and its impact on digestive disorders. METHODS: This study employed data from the UK Biobank, comprising 405,394 individuals of European ancestry, who underwent assessments of both left- and right- hand grip strength at baseline. We calculated the relative hand grip strength (RHGS), defined as the average hand grip strength adjusted for body mass index (BMI). Subsequently, we performed genome-wide association study (GWAS) to identify RHGS-linked variants and genes. We evaluated RHGS’s impact on digestive disorders using linkage disequilibrium score regression (LDSC), Mendelian randomization (MR), Polygenic risk score (PRS), regression models, and interaction analyses. RESULTS: GWAS of 405,394 Europeans identified 1,111 independent SNPs across 226 autosomal loci and 407 genes associated with RHGS. TWAS with skeletal-muscle eQTLs prioritized genes, including L3MBTL3, CEP192 and NUCKS1, highly expressed in type I/II myocytes and mesenchymal cells. LDSC revealed significant negative genetic correlations between RHGS and abdominal hernia (rg = -0.121, p = 5.00 × 10⁻⁴), diaphragmatic hernia (rg = -0.155, p = 6.33 × 10⁻⁶) and diverticular intestine (rg = -0.141, p = 3.85 × 10⁻¹⁰). MR indicated that one-unit higher genetically predicted RHGS reduced odds of diaphragmatic hernia (OR = 0.45, 95% CI 0.25–0.82), diverticular intestine (OR = 0.42, 0.26–0.66), NAFLD (OR = 0.49, 0.29–0.83) and peptic ulcer (OR = 0.54, 0.31–0.97). Each standard-deviation increase in RHGS PRS was associated with lower risks of abdominal hernia (OR = 0.98), diaphragmatic hernia (OR = 0.96) and diverticular intestine (OR = 0.98) after full adjustment. Gene-environment analyses showed diabetes, hyperlipidemia and smoking attenuated the protective effects from elevated RHGS, whereas cardioprotective diet and higher fiber intake showed synergistic protection on abdominal hernia, diaphragmatic hernia and diverticular intestine. CONCLUSION: We identified multiple RHGS-associated loci enriched in skeletal muscle. Genetically high RHGS inversely correlated with risks of abdominal hernia, diaphragmatic hernia and diverticular intestine. RHGS polygenic risk score enables risk stratification, and its effects are modulated by diet and common comorbidities.