Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma

John C. Chambers, Weihua Zhang, Joban Sehmi, Xinzhong Li, Mark N. Wass, Pim Van Der Harst, Hilma Holm, Serena Sanna, Maryam Kavousi, Sebastian E. Baumeister, Lachlan J. Coin, Guohong Deng, Christian Gieger, Nancy L. Heard-Costa, Jouke Jan Hottenga, Brigitte Kühnel, Vinod Kumar, Vasiliki Lagou, Liming Liang, Jian'An LuanPedro Marques Vidal, Irene Mateo Leach, Paul F. O'Reilly, John F. Peden, Nilufer Rahmioglu, Pasi Soininen, Elizabeth K. Speliotes, Xin Yuan, Gudmar Thorleifsson, Behrooz Z. Alizadeh, Larry D. Atwood, Ingrid B. Borecki, Morris J. Brown, Pimphen Charoen, Francesco Cucca, Debashish Das, Eco J C De Geus, Anna L. Dixon, Angela Döring, Georg Ehret, Gudmundur I. Eyjolfsson, Martin Farrall, Nita G. Forouhi, Nele Friedrich, Wolfram Goessling, Daniel F. Gudbjartsson, Tamara B. Harris, Anna Liisa Hartikainen, Simon Heath, Gideon M. Hirschfield, Albert Hofman, Georg Homuth, Elina Hyppönen, Harry L A Janssen, Toby Johnson, Antti J. Kangas, Ido P. Kema, Jens P. Kühn, Sandra Lai, Mark Lathrop, Markus M. Lerch, Yun Li, T. Jake Liang, Jing Ping Lin, Ruth J F Loos, Nicholas G. Martin, Miriam F. Moffatt, Grant W. Montgomery, Patricia B. Munroe, Kiran Musunuru, Yusuke Nakamura, Christopher J. O'Donnell, Isleifur Olafsson, Brenda W. Penninx, Anneli Pouta, Bram P. Prins, Inga Prokopenko, Ralf Puls, Aimo Ruokonen, Markku J. Savolainen, David Schlessinger, Jeoffrey N L Schouten, Udo Seedorf, Srijita Sen-Chowdhry, Katherine A. Siminovitch, Johannes H. Smit, Timothy D. Spector, Wenting Tan, Tanya M. Teslovich, Taru Tukiainen, Andre G. Uitterlinden, Melanie M. Van Der Klauw, Ramachandran S. Vasan, Chris Wallace, Henri Wallaschofski, H. Erich Wichmann, Gonneke Willemsen, Peter Würtz, Chun Xu, Laura M. Yerges-Armstrong, Goncalo R. Abecasis, Kourosh R. Ahmadi, Dorret I. Boomsma, Mark Caulfield, William O. Cookson, Cornelia M. Van Duijn, Philippe Froguel, Koichi Matsuda, Mark I. McCarthy, Christa Meisinger, Vincent Mooser, Kirsi H. Pietiláinen, Gunter Schumann, Harold Snieder, Michael J E Sternberg, Ronald P. Stolk, Howard C. Thomas, Unnur Thorsteinsdottir, Manuela Uda, Gérard Waeber, Nicholas J. Wareham, Dawn M. Waterworth, Hugh Watkins, John B. Whitfield, Jacqueline C M Witteman, Bruce H R Wolffenbuttel, Caroline S. Fox, Mika Ala-Korpela, Kari Stefansson, Peter Vollenweider, Henry Völzke, Eric E. Schadt, James Scott, Marjo Riitta Járvelin, Paul Elliott, Jaspal S. Kooner

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    323 Citations (Scopus)

    Abstract

    Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10-8 to P = 10-190). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.

    Original languageEnglish
    Pages (from-to)1131-1138
    Number of pages8
    JournalNature Genetics
    Volume43
    Issue number11
    DOIs
    Publication statusPublished - 1 Nov 2011

    ASJC Scopus subject areas

    • Genetics

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