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

• Published in: Nature Communications
• Main Authors: Pazoki, Raha, Vujkovic, Marijana, Elliott, Joshua, Evangelou, Evangelos, Gill, Dipender, Ghanbari, Mohsen, van der Most, Peter J., Pinto, Rui Climaco, Wielscher, Matthias, Farlik, Matthias, Zuber, Verena, de Knegt, Robert J., Snieder, Harold, Uitterlinden, André G., Lynch, Julie A., Jiang, Xiyun, Said, Saredo, Kaplan, David E., Lee, Kyung Min, Serper, Marina, Carr, Rotonya M., Tsao, Philip S., Atkinson, Stephen R., Dehghan, Abbas, Tzoulaki, Ioanna, Ikram, M. Arfan, Herzig, Karl-Heinz, Järvelin, Marjo-Riitta, Alizadeh, Behrooz Z., O’Donnell, Christopher J., Saleheen, Danish, Voight, Benjamin F., Chang, Kyong-Mi, Thursz, Mark R., Elliott, Paul
• Other Authors: RCUK | Medical Research Council
• Format: Article in Journal/Newspaper
• Language: English
• Published: Springer Science and Business Media LLC 2021
• Subjects: General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry; Northern Finland
• Online Access: http://dx.doi.org/10.1038/s41467-021-22338-2; http://www.nature.com/articles/s41467-021-22338-2.pdf; http://www.nature.com/articles/s41467-021-22338-2

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.