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

Rita P Middelberg, Beben Benyamin, Marleen H M de Moor, Nicole M Warrington, Scott Gordon, Anjali K Henders, Sarah E Medland, Dale R Nyholt, Eco J C de Geus, Jouke J Hottenga, Gonneke Willemsen, Lawrence J Beilin, Trevor A Mori, Margaret J Wright, Andrew C Heath, Pamela A F Madden, Dorret I Boomsma, Craig E Pennell, Grant W Montgomery, Nicholas G MartinJohn B Whitfield

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)446-55
Number of pages10
JournalHuman Molecular Genetics
Volume21
Issue number2
DOIs
Publication statusPublished - 15 Jan 2012

Bibliographical note

© The Author 2011. Published by Oxford University Press. All rights reserved.

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