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

## TL;DR

This study finds that genetic factors influencing hand grip strength are linked to lower risks of certain digestive disorders like hernias and diverticulitis.

## Contribution

The study identifies novel genetic loci and genes associated with relative handgrip strength and shows their protective effects against gastrointestinal disorders.

## Key findings

- GWAS identified 1,111 SNPs and 407 genes linked to relative handgrip strength.
- Higher genetic handgrip strength is inversely associated with risks of abdominal hernia, diaphragmatic hernia, and diverticular intestine.
- Diet and comorbidities like diabetes and hyperlipidemia modify the protective effects of handgrip strength on digestive disorders.

## Abstract

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.

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.

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.

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.

The schematics of the study pipeline in the investigation of RHGS GWAS and the follow-up post-GWAS analyses for clinical relevance. RHGS: relative hand grip strength; GWAS: genome-wide association study.

The online version contains supplementary material available at 10.1186/s12876-026-04624-9.

1. GWAS revealed hundreds of independent SNPs and genes linked to RHGS.

2. TWAS and colocalization prioritized multiple skeletal muscle related-genes associated with RHGS.

3. RHGS showed significant negative genetic correlations and inverse causation with many digestive disorders.

4. Polygenic risk score for RHGS predicted decreased risk of abdominal hernia, diaphragmatic hernia and diverticular intestine.

5. Lifestyle factors and comorbidities might modify genetic associations between RHGS and digestive diseases.

The online version contains supplementary material available at 10.1186/s12876-026-04624-9.