Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes.

Journal Article (Journal Article)

Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.

Full Text

Duke Authors

Cited Authors

  • Pazoki, R; Vujkovic, M; Elliott, J; Evangelou, E; Gill, D; Ghanbari, M; van der Most, PJ; Pinto, RC; Wielscher, M; Farlik, M; Zuber, V; de Knegt, RJ; Snieder, H; Uitterlinden, AG; Lifelines Cohort Study, ; Lynch, JA; Jiang, X; Said, S; Kaplan, DE; Lee, KM; Serper, M; Carr, RM; Tsao, PS; Atkinson, SR; Dehghan, A; Tzoulaki, I; Ikram, MA; Herzig, K-H; Järvelin, M-R; Alizadeh, BZ; O'Donnell, CJ; Saleheen, D; Voight, BF; Chang, K-M; Thursz, MR; Elliott, P; VA Million Veteran Program,

Published Date

  • May 10, 2021

Published In

Volume / Issue

  • 12 / 1

Start / End Page

  • 2579 -

PubMed ID

  • 33972514

Pubmed Central ID

  • PMC8110798

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-021-22338-2


  • eng

Conference Location

  • England