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.

Figure 1.

Comparison of the magnitude and direction of allelic effects on GGT activity at the GGT1 locus in adults (red diamonds) and adolescents (blue squares). Gene locations are shown below the main panel, with the linkage disequilibrium (R²) between SNPs below that. Points shown are the unstandardized betas for the minor-allele effect on log-transformed GGT activity in an additive model, and bars show standard errors. Between rs5760485 at 23 316 473 bp and rs2001180 at 23 334 206 bp (shaded region A), the allelic effects are in opposite directions in adults and adolescents. Between rs6004233 at 23 404 863 bp and rs5760590 at 23 420 768 bp (shaded region B), the allelic effects in adults are negligible but those for adolescents are similar to those for the 23.316–23.334 Mbp region.

Figure 2.

Allelic effects at rs6519519 on log₁₀GGT, by age group; QIMR data by age, and results from replication in RAINE adolescent and NTR adult studies. Error bars show SE for each estimated beta.

Figure 3.

Network of genes containing SNPs affecting GGT at P < 0.001 (pink blocks) or P < 5 × 10⁻⁸ (red blocks), emphasizing HNF connections. (Details of the genes in this network, the most significant SNPs in each gene and their P-values are given in Supplementary Material, Table S7.)