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

Author

Listed:
  • Raha Pazoki

    (School of Public Health
    Brunel University London)

  • Marijana Vujkovic

    (Corporal Michael J. Crescenz VA Medical Center
    University of Pennsylvania)

  • Joshua Elliott

    (School of Public Health
    Royal Surrey County Hospital)

  • Evangelos Evangelou

    (School of Public Health
    University of Ioannina Medical School)

  • Dipender Gill

    (School of Public Health
    Imperial College London)

  • Mohsen Ghanbari

    (Erasmus University Medical Center Rotterdam
    Mashhad University of Medical Sciences)

  • Peter J. van der Most

    (University Medical Center Groningen)

  • Rui Climaco Pinto

    (School of Public Health
    Imperial College London)

  • Matthias Wielscher

    (School of Public Health
    Medical University of Vienna)

  • 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
    University of Massachusetts)

  • Xiyun Jiang

    (Brunel University London)

  • Saredo Said

    (School of Public Health)

  • David E. Kaplan

    (Corporal Michael J. Crescenz VA Medical Center
    University of Pennsylvania)

  • Kyung Min Lee

    (VA Salt Lake City Health Care System
    University of Utah)

  • Marina Serper

    (Corporal Michael J. Crescenz VA Medical Center
    University of Pennsylvania)

  • Rotonya M. Carr

    (Corporal Michael J. Crescenz VA Medical Center
    University of Pennsylvania)

  • Philip S. Tsao

    (VA Palo Alto Health Care System
    Stanford University)

  • Stephen R. Atkinson

    (Digestion & Reproduction, Imperial College London)

  • Abbas Dehghan

    (School of Public Health
    Imperial College London)

  • Ioanna Tzoulaki

    (School of Public Health
    University of Ioannina Medical School)

  • M. Arfan Ikram

    (Erasmus University Medical Center Rotterdam)

  • Karl-Heinz Herzig

    (Oulu University
    Oulu University Hospital
    Poznan University of Medical Sciences)

  • Marjo-Riitta Järvelin

    (School of Public Health
    Oulu University
    Brunel University London
    Oulu University Hospital)

  • Behrooz Z. Alizadeh

    (University Medical Center Groningen)

  • Christopher J. O’Donnell

    (VA Boston Healthcare System
    Harvard Medical School
    Brigham Women’s Hospital)

  • Danish Saleheen

    (Columbia University)

  • Benjamin F. Voight

    (Corporal Michael J. Crescenz VA Medical Center
    University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Kyong-Mi Chang

    (Corporal Michael J. Crescenz VA Medical Center
    University of Pennsylvania)

  • Mark R. Thursz

    (Digestion & Reproduction, Imperial College London)

  • Paul Elliott

    (School of Public Health
    Imperial College London
    Imperial College London
    Imperial College London)

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.

Suggested Citation

  • 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 Zub, 2021. "Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22338-2
    DOI: 10.1038/s41467-021-22338-2
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