Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes
Raha Pazoki, Marijana Vujković, Joshua Elliott, Εvangelos Εvangelou, Dipender Gill, Mohsen Ghanbari, Peter J. van der Most, Rui Pinto, Matthias Wielscher, Matthias Farlik, Verena Zuber, Robert J. de Knegt, Harold Snieder, André G. Uitterlinden, Lifelines Cohort Study, H. Marike Boezen, Lude Franke, Pim van der Harst, Gerjan Navis, Marianne G. Rots, Morris A. Swertz, Bruce H. R. Wolffenbuttel, Cisca Wijmenga, 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 Thursz, Paul Elliott, the VA Million Veteran Program, Zuhair K. Ballas, Sujata Bhushan, Edward J. Boyko, David Cohen, John Concato, Michaela Aslan, Hongyu Zhao, Joseph I. Constans, Louis J. Dell’Italia, Joseph Fayad, Ronald Fernando, Hermes Flórez, Melinda A. Gaddy, Saib Gappy, Gretchen Gibson, Michael Godschalk, Jennifer A. Greco, Samir Gupta, Salvador Gutierrez, Kimberly Hammer, Mark B. Hamner, John B. Harley, Adriana M. Hung, Mostaqul Huq, Robin A. Hurley, Pran Iruvanti, Douglas Ivins, Frank J. Jacono, Darshana Jhala, Laurence S. Kaminsky, Jon B. Klein, Suthat Liangpunsakul, Jack Lichy, Jennifer Moser, Grant D. Huang, Sumitra Muralidhar, Stephen Mastorides, Roy O. Mathew, Kristin Mattocks, Rachel McArdle, Paul N. Meyer, Laurence J. Meyer, Jonathan P. Moorman, Timothy R. Morgan, Maureen Murdoch, Olaoluwa Okusaga, Krisann K. Oursler, Nora Ratcliffe, Michael Rauchman, R. Brooks Robey, George Ross, Richard J. Servatius, Satish Sharma, Scott E. Sherman, Elif Sonel
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.