1. Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes.
- Author
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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, 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 KH, Järvelin MR, Alizadeh BZ, O'Donnell CJ, Saleheen D, Voight BF, Chang KM, Thursz MR, and Elliott P
- Subjects
- Aged, Alanine Transaminase blood, Alkaline Phosphatase blood, Cardiovascular Diseases enzymology, Cohort Studies, Databases, Genetic, Female, Gene Expression Regulation, Enzymologic genetics, Genetic Predisposition to Disease, Genetic Testing, Genome-Wide Association Study, Humans, Insulin Resistance genetics, Lipid Metabolism genetics, Liver metabolism, Male, Mendelian Randomization Analysis, Metabolic Diseases enzymology, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, White People, gamma-Glutamyltransferase blood, Alanine Transaminase genetics, Alkaline Phosphatase genetics, Cardiovascular Diseases genetics, Liver enzymology, Metabolic Diseases genetics, gamma-Glutamyltransferase genetics
- 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.
- Published
- 2021
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