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

Lifelines Cohort Study, VA Million Veteran Program, Raha Pazoki*, Marijana Vujkovic, Joshua Elliott, Evangelos Evangelou, Dipender Gill, Mohsen Ghanbari, Peter J. van der Most, Rui Climaco Pinto, Matthias Wielscher, Matthias Farlik, Verena Zuber, Robert J. de Knegt, Harold Snieder, André G. Uitterlinden, Julie A. Lynch, Xiyun Jiang, Saredo Said, David E. KaplanKyung Min Lee, Marina Serper, Rotonya M. Carr, Philip S. Tsao, Stephen R. Atkinson, Abbas Dehghan, Ioanna Tzoulaki, M. Arfan Ikram, Karl Heinz Herzig, Marjo Riitta Järvelin, Behrooz Z. Alizadeh, Christopher J. O'Donnell, Danish Saleheen, Benjamin F. Voight, Kyong Mi Chang, Mark R. Thursz, Paul Elliott

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Plasma levels of liver enzymes provide insights into hepatic function and related diseases. Here, the authors perform a genome-wide association study on three liver enzymes, identifying genetic variants associated with their plasma concentration as well as links to metabolic and cardiovascular diseases.

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.

Original languageEnglish
Article number2579
Number of pages12
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 10-May-2021

Keywords

  • GENOME-WIDE ASSOCIATION
  • LD SCORE REGRESSION
  • MENDELIAN RANDOMIZATION
  • DISEASE
  • METAANALYSIS
  • BIOBANK
  • RISK
  • HERITABILITY
  • POPULATION
  • HEALTH

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