Multi-ancestry Genome-wide Association Study of Creatine Kinase Highlights the Genetic Basis of Muscle Damage

Serum creatine kinase (CK) is a routinely measured biomarker of muscle damage, yet the genetic factors underlying inter-individual variation in CK levels remain poorly defined. Here we present the largest multi-ancestry genome-wide association meta-analysis of serum CK to date, comprising 237,255 participants spanning Admixed American, African American, East Asian, European and Middle Eastern populations. We identify 107 independent loci at genome-wide significance (P<5x10 ^-8 ), 98 of which are previously unreported, with pronounced enrichment for genes expressed in skeletal and cardiac muscle and overlap with pathways related to muscle structure and function. Notably, eight loci map to genes implicated in Mendelian myopathies, underscoring a continuum from common regulatory variation to rare pathogenic mutations. Integrative quantitative trait locus (QTL)-based Mendelian randomization and colocalization implicate several genes in CK regulation, most prominently SMAD3 , KLF5 and STAT3 within the transforming growth factor beta signalling pathway. CK levels show positive genetic correlations with traits reflecting tissue damage and muscle mass, and negative correlations with C-reactive protein, indicating pleiotropic effects on muscle biology and enzyme clearance. Together, these findings delineate the genetic architecture of serum CK across diverse populations and provide insight into the genetic basis of muscle-damage risk and subclinical CK elevation.