Loci affecting gamma-glutamyl transferase in adults and adolescents show age × SNP interaction and cardiometabolic disease associations

Abstract

Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in an intergenic region of chromosome 1, P = 3.9 × 10⁻⁸; rs944002 in C14orf73 on chromosome 14, P = 4.7 × 10⁻¹³; rs340005 in RORA on chromosome 15, P = 2.4 × 10⁻⁸), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum P_HET = 5.6 × 10⁻¹² at rs6519520). Pathway analysis of significant and suggestive single-nucleotide polymorphism associations showed significant overlap between genes affecting GGT and those affecting common metabolic and inflammatory diseases, and identified the hepatic nuclear factor (HNF) family as controllers of a network of genes affecting GGT. Our results reinforce the disease associations of GGT and demonstrate that control by the GGT1 locus varies with age.