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

2011; Nature Portfolio; Volume: 43; Issue: 11 Linguagem: Inglês

10.1038/ng.970

1546-1718

John C. Chambers, Wei Zhang, Joban Sehmi, Man Li, Mark N. Wass, Pim van der Harst, Hilma Hólm, Serena Sanna, Maryam Kavousi, Sebastian E. Baumeister, Lachlan Coin, Guohong Deng, Christian Gieger, Nancy L. Heard‐Costa, Jouke‐Jan Hottenga, Brigitte Kühnel, Vinod Kumar, Vasiliki Lagou, Liming Liang, Jian'an Luan, Pedro Marques‐Vidal, Irene Mateo Leach, Paul F. O’Reilly, John F. Peden, Nilüfer Rahmioğlu, Pasi Soininen, Elizabeth K. Speliotes, Xin Yuan, Guðmar Þorleifsson, Behrooz Z. Alizadeh, Larry D. Atwood, Ingrid B. Borecki, Matthew A. Brown, Pimphen Charoen, Francesco Cucca, Debashish Das, Eco J. C. de Geus, Anna Dixon, Angela Döring, Georg Ehret, Guðmundur I. Eyjólfsson, Martin Farrall, Nita G. Forouhi, Nele Friedrich, Wolfram Goessling, Daníel F. Guðbjartsson, 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‐Peter 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, Yan V. Sun, Yusuke Nakamura, Christopher J. O’Donnell, Isleifur Olafsson, Brenda W.J.H. Penninx, Anneli Pouta, Bram P. Prins, Inga Prokopenko, Ralf Puls, Aimo Ruokonen, Markku J. Savolainen, David Schlessinger, Jeoffrey Schouten, Udo Seedorf, Srijita Sen‐Chowdhry, Katherine A. Siminovitch, Johannes H. Smit, Timothy D Spector, Wenting Tan, Tanya M. Teslovich, Taru Tukiainen, André 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, Gonçalo R. Abecasis, Kourosh R. Ahmadi, Marcus Dörr, Mark J. Caulfield, William Cookson, Cornelia M. van Duijn, Philippe Froguel, Koichi Matsuda, Mark I. McCarthy, Christa Meisinger, Vincent Mooser, Kirsi H. Pietiläinen, Günter Schumann, Harold Snieder, Michael J.E. Sternberg, Ronald P. Stolk, Howard C. Thomas, Unnur Þorsteinsdóttir, Manuela Uda, Gérard Waeber, Nicholas J. Wareham, Dawn Waterworth, Hugh Watkins, John B. Whitfield, Jacqueline C.M. Witteman, Bruce H. R. Wolffenbuttel, Caroline S. Fox, Mika Ala‐Korpela, Kári Stéfansson, Péter Vollenweider, Henry Völzke, Eric E. Schadt, James Scott, Marjo‐Riitta Järvelin, Paul Elliott, Jaspal S. Kooner,

Hepatitis B Virus Studies

John Chambers and colleagues report a genome-wide association study for markers of liver function. They identify 42 loci associated with concentrations of one or more liver enzymes in plasma, and use a range of functional genomic analyses to suggest candidate genes at these loci. 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.