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 de 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; Paul Elliott; VA Million Veteran Program

doi:10.1038/s41467-021-22338-2

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

Journal article

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Peer reviewed

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, …

Nature communications, Vol.12(1), pp.2579-2579

05/10/2021

DOI: 10.1038/s41467-021-22338-2

PMCID: PMC8110798

PMID: 33972514

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https://doi.org/10.1038/s41467-021-22338-2View

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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.

Aged

Alanine Transaminase - blood

Alanine Transaminase - genetics

Alkaline Phosphatase - blood

Alkaline Phosphatase - genetics

Cardiovascular Diseases - enzymology

Cardiovascular Diseases - genetics

Cohort Studies

Databases, Genetic

Female

gamma-Glutamyltransferase - blood

gamma-Glutamyltransferase - genetics

Gene Expression Regulation, Enzymologic - genetics

Genetic Predisposition to Disease

Genetic Testing

Genome-Wide Association Study

Humans

Insulin Resistance - genetics

Lipid Metabolism - genetics

Liver - enzymology

Liver - metabolism

Male

Mendelian Randomization Analysis

Metabolic Diseases - enzymology

Metabolic Diseases - genetics

Middle Aged

Polymorphism, Single Nucleotide

Risk Factors

Whites

Details

Title: Subtitle: Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes
Creators: Raha Pazoki - Brunel University of London
Marijana Vujkovic - University of Pennsylvania
Joshua Elliott - Royal Surrey County Hospital
Evangelos Evangelou - University of Ioannina
Dipender Gill - British Heart Foundation
Mohsen Ghanbari - Erasmus MC
Peter J van der Most - University Medical Center Groningen
Rui Climaco Pinto - UK Dementia Research Institute
Matthias Wielscher - Medical University of Vienna
Matthias Farlik - Medical University of Vienna
Verena Zuber - MRC Centre
Robert J de Knegt - Erasmus MC
Harold Snieder - University Medical Center Groningen
André G Uitterlinden - Erasmus MC
Julie A Lynch - University of Massachusetts Boston
Xiyun Jiang - Brunel University of London
Saredo Said - MRC Centre
David E Kaplan - Philadelphia VA Medical Center
Kyung Min Lee - University of Utah
Marina Serper - Philadelphia VA Medical Center
Rotonya M Carr - Philadelphia VA Medical Center
Philip S Tsao - Stanford University
Stephen R Atkinson - Imperial College London
Abbas Dehghan - UK Dementia Research Institute
Ioanna Tzoulaki - University of Ioannina
M Arfan Ikram - Erasmus MC
Karl-Heinz Herzig - Oulu University Hospital
Marjo-Riitta Järvelin - MRC Centre
Behrooz Z Alizadeh - University Medical Center Groningen
Christopher J O'Donnell - VA Boston Healthcare System
Danish Saleheen - Columbia University
Benjamin F Voight - Philadelphia VA Medical Center
Kyong-Mi Chang - Philadelphia VA Medical Center
Mark R Thursz - Imperial College London
Paul Elliott - MRC Centre
VA Million Veteran Program
Contributors: Zuhair K Ballas (Contributor) - University of Iowa, Immunology
Resource Type: Journal article
Publication Details: Nature communications, Vol.12(1), pp.2579-2579
DOI: 10.1038/s41467-021-22338-2
PMID: 33972514
PMCID: PMC8110798
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: R56 DK101478 / NIDDK NIH HHS Department of Health MR/L01632X/1 / Medical Research Council MR/S019669/1 / Medical Research Council MR/R0265051/1 / Medical Research Council RL1 MH083268 / NIMH NIH HHS MC_QA137853 / Medical Research Council MR/R023484/1 / Medical Research Council MR/S03658X/1 / Medical Research Council MC_PC_17228 / Medical Research Council MR/L01341X/1 / Medical Research Council R01 HL087679 / NHLBI NIH HHS K23 DK115897 / NIDDK NIH HHS SP/13/2/30111 / British Heart Foundation
Language: English
Date published: 05/10/2021
Academic Unit: Immunology; Internal Medicine
Record Identifier: 9984360150302771

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