Journal Article

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

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

2021

Overview

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. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/43 / 631/208/205/2138 / 692/53/2423 / 692/699/1503/1607/2750 / Aged / Alanine / Alanine transaminase / Alanine Transaminase - blood / Alanine Transaminase - genetics / Alkaline phosphatase / Alkaline Phosphatase - blood / Alkaline Phosphatase - genetics / Body mass index / Body size / Cardiovascular disease / Cardiovascular diseases / Cardiovascular Diseases - enzymology / Cardiovascular Diseases - genetics / Cohort Studies / Coronary artery disease / Databases, Genetic / Enzymes / Female / gamma-Glutamyltransferase - blood / gamma-Glutamyltransferase - genetics / Gene Expression Regulation, Enzymologic - genetics / Gene set enrichment analysis / Genetic analysis / Genetic diversity / Genetic Predisposition to Disease / Genetic Testing / Genetic variance / Genome-wide association studies / Genome-Wide Association Study / Genomes / Heart diseases / Humanities and Social Sciences / Humans / Insulin / Insulin resistance / Insulin Resistance - genetics / Ischemia / Lipid metabolism / Lipid Metabolism - genetics / Lipids / Liver / Liver - enzymology / Liver - metabolism / Liver diseases / Male / Mendelian Randomization Analysis / Metabolic Diseases - enzymology / Metabolic Diseases - genetics / Metabolic disorders / Metabolism / Middle Aged / multidisciplinary / Plasma levels / Polymorphism, Single Nucleotide / Risk analysis / Risk Factors / Science / Science (multidisciplinary) / Serum levels / Single-nucleotide polymorphism / Transaminase / White People / γ-Glutamyltransferase