Colocalization and functional analyses identify <i>GBE1</i> as a gene linking muscle strength and cardiometabolic fitness

Handgrip strength is a proxy for muscular fitness, an indicator for general health status, and is associated with cardiometabolic health. The mechanisms connecting handgrip strength to skeletal muscle function are incompletely understood. We applied integrated linkage-disequilibrium-adjusted colocalization analysis of genome-wide association study summary statistics for handgrip strength, combined with expression and splicing quantitative trait loci from skeletal muscle, and identified glycogen branching enzyme 1 (<i>GBE1</i>) as a candidate gene for handgrip strength. CRISPR-interference knockdown of <i>GBE1</i> in immortalized human skeletal muscle cells (HMCL-7304) demonstrated decreased glycogen content and accumulation of polyglucosan bodies. Knockdown of <i>GBE1</i> led to increased oxygen consumption rate, oxidative stress, and changes in mitochondrial morphology. Transcriptomic profiling of <i>GBE1</i> knockdown cells identified upregulation of the human superoxide dismutase 2 and enrichment of pathways related to muscle contraction and oxidative stress responses. These functional genomic analyses prioritize <i>GBE1</i> as a muscle-relevant candidate gene for handgrip strength and provide mechanistic insights to muscle fitness.<b>NEW & NOTEWORTHY</b> Colocalization of genome-wide association study (GWAS) loci with quantitative trait loci (QTL) in skeletal muscle tissue identified <i>GBE1</i> as a candidate for handgrip strength. Cellular phenotypes with <i>GBE1</i> knockdown in immortalized human skeletal muscle cells include decreased glycogen content, accumulation of polyglucosan bodies, changes in mitochondrial function and morphology, and increased expression of reactive oxygen species (ROS) scavengers. Transcriptomic changes suggest a role for <i>GBE1</i> in muscle contraction and oxidative stress-mediated responses.