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

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. Knegt, Harold Snieder, André G. Uitterlinden, Julie A. Lynch, Xiyun Jiang, Saredo Said, David E. Kaplan, Kyung 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 and Paul Elliott ()
Additional contact information
Raha Pazoki: School of Public Health
Marijana Vujkovic: Corporal Michael J. Crescenz VA Medical Center
Joshua Elliott: School of Public Health
Evangelos Evangelou: School of Public Health
Dipender Gill: School of Public Health
Mohsen Ghanbari: Erasmus University Medical Center Rotterdam
Peter J. van der Most: University Medical Center Groningen
Rui Climaco Pinto: School of Public Health
Matthias Wielscher: School of Public Health
Matthias Farlik: Medical University of Vienna
Verena Zuber: School of Public Health
Robert J. Knegt: Erasmus University Medical Center Rotterdam
Harold Snieder: University Medical Center Groningen
André G. Uitterlinden: Erasmus University Medical Center Rotterdam
Julie A. Lynch: VA Salt Lake City Health Care System
Xiyun Jiang: Brunel University London
Saredo Said: School of Public Health
David E. Kaplan: Corporal Michael J. Crescenz VA Medical Center
Kyung Min Lee: VA Salt Lake City Health Care System
Marina Serper: Corporal Michael J. Crescenz VA Medical Center
Rotonya M. Carr: Corporal Michael J. Crescenz VA Medical Center
Philip S. Tsao: VA Palo Alto Health Care System
Stephen R. Atkinson: Digestion & Reproduction, Imperial College London
Abbas Dehghan: School of Public Health
Ioanna Tzoulaki: School of Public Health
M. Arfan Ikram: Erasmus University Medical Center Rotterdam
Karl-Heinz Herzig: Oulu University
Marjo-Riitta Järvelin: School of Public Health
Behrooz Z. Alizadeh: University Medical Center Groningen
Christopher J. O’Donnell: VA Boston Healthcare System
Danish Saleheen: Columbia University
Benjamin F. Voight: Corporal Michael J. Crescenz VA Medical Center
Kyong-Mi Chang: Corporal Michael J. Crescenz VA Medical Center
Mark R. Thursz: Digestion & Reproduction, Imperial College London
Paul Elliott: School of Public Health

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22338-2

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