Multi-ancestry Genome-wide Association Study of Serum Creatine Kinase Implicates Myopathy Genes and Muscle Pathways

Background: 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.

Methods: Here we present a large multi-ancestry genome-wide association meta-analysis of serum CK, comprising 237,255 participants spanning Admixed American, African American, East Asian, European and Middle Eastern populations.

Findings: 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 as well as muscle mass and strength, and negative correlations with C-reactive protein, indicating pleiotropic effects from muscle biology and enzyme clearance.

Interpretation: These findings delineate the genetic architecture of serum CK across diverse populations and highlight muscle-related pathways contributing to CK variation.