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

Authors:
Antti Kangas
Antti Kangas
Nightingale Health Ltd.
CTO
Helsinki | Finland
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 Luan Pedro 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 Pietiläinen 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 Järvelin Paul Elliott Jaspal S Kooner

Nat Genet 2011 Oct 16;43(11):1131-8. Epub 2011 Oct 16.

Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, UK.

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.

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October 2011
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