Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes
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. ,   Lifelines Cohort Study, Boezen H. Marike , Franke Lude , van der Harst Pim , Navis Gerjan , Rots Marianne , Swertz Morris , Wolffenbuttel Bruce H. R. , Wijmenga Cisca , 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 ,   the VA Million Veteran Program, Ballas Zuhair K. , Bhushan Sujata , Boyko Edward J. , Cohen David M. , Concato John , Aslan Michaela , Zhao Hongyu , Constans Joseph I. , Dellitalia Louis J. , Fayad Joseph M. , Fernando Ronald S. , Florez Hermes J. , Gaddy Melinda A. , Gappy Saib S. , Gibson Gretchen , Godschalk Michael , Greco Jennifer A. , Gupta Samir , Gutierrez Salvador , Hammer Kimberly D. , Hamner Mark B. , Harley John B. , Hung Adriana M. , Huq Mostaqul , Hurley Robin A. , Iruvanti Pran R. , Ivins Douglas J. , Jacono Frank J. , Jhala Darshana N. , Kaminsky Laurence S. , Klein Jon B. , Liangpunsakul Suthat , Lichy Jack H. , Moser Jennifer , Huang Grant D. , Muralidhar Sumitra , Mastorides Stephen M. , Mathew Roy O. , Mattocks Kristin M. , McArdle Rachel , Meyer Paul N. , Meyer Laurence J. , Moorman Jonathan P. , Morgan Timothy R. , Murdoch Maureen , Okusaga Olaoluwa O. , Oursler Kris-Ann K. , Ratcliffe Nora R. , Rauchman Michael I. , Robey R. Brooks , Ross George W. , Servatius Richard J. , Sharma Satish C. , Sherman Scott E. , Sonel Elif , Sriram Peruvemba , Stapley Todd , Striker Robert T. , Tandon Neeraj , Villareal Gerardo , Wallbom Agnes S. , Wells John M. , Whittle Jeffrey C. , Whooley Mary A. , Wilson Peter W. , Sun Yan V. , Xu Junzhe , Yeh Shing-Shing , Connor Todd , Argyres Dean P. , Hauser Elizabeth R. , Beckham Jean C. , Stephens Brady , Aguayo Samuel M. , Ahuja Sunil K. , Pyarajan Saiju , Cho Kelly , Gaziano J. Michael , Kinlay Scott , Nguyen Xuan-Mai T. , Brewer Jessica V. , Brophy Mary T. , Do Nhan V. , Humphries Donald E. , Selva Luis E. , Shayan Shahpoor , Whitbourne Stacey B. , Breeling Jim L. , Romero J. P. Casas , Ramoni Rachel B. 
Published: May 2021

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.