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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 (LD)-adjusted colocalization analysis of genome-wide association study (GWAS) summary statistics for handgrip strength combined with expression and splicing quantitative trait loci from skeletal muscle and identified Glycogen branching enzyme 1 (GBE1) as a candidate gene for handgrip strength. CRISPRi knockdown of GBE1 in immortalized human skeletal muscle cells (HMCL-7304) demonstrated decreased glycogen content and accumulation of polyglucosan bodies. Knockdown of GBE1 led to increased oxygen consumption rate, oxidative stress, and changes in mitochondrial morphology. Transcriptomic profiling of GBE1 knockdown cells identified up-regulation of the human superoxide dismutase 2 (SOD2) and enrichment of pathways related to muscle contraction and oxidative stress responses. These functional genomic analyses prioritize GBE1 as a muscle-relevant candidate gene for handgrip strength and provide mechanistic insights to muscle fitness.