Multi-cohort genome-wide association analyses reveal loci underlying circulating liver enzyme levels in African-ancestry populations

Abstract Liver enzymes are critical biomarkers of hepatic metabolism, injury, and systemic homeostasis. Their genetic architecture remains understudied in African-ancestry populations. We addressed this knowledge gap by conducting genome-wide analyses of four liver enzymes in over 55,000 individuals of African ancestry from six cohorts across sub-Saharan Africa, the United States, and the United Kingdom. We identified 31 significant loci, of which 14 were novel, including TMEM64 and CRYL1 for alkaline phosphatase, IMMP2L for alanine aminotransferase, and PDE4D for gamma-glutamyl transferase. Several novel variants exhibited high allele frequencies in African-ancestry populations but were rare or absent in other global populations. Functional annotation indicated that lead variants overlapped liver-active regulatory regions, histone marks, and hepatocyte eQTLs. Colocalization and enrichment analyses implicated pathways related to lipid and carbohydrate metabolism, glycosylation, and immune function. Our findings expand the catalog of genetic variants influencing liver enzymes and advance understanding of the biological mechanisms underlying liver function.