Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Oct 16;43(11):1131-8.
doi: 10.1038/ng.970.

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

John C Chambers  1 , 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; Alcohol Genome-wide Association (AlcGen) Consortium; Diabetes Genetics Replication and Meta-analyses (DIAGRAM+) Study; Genetic Investigation of Anthropometric Traits (GIANT) Consortium; Global Lipids Genetics Consortium; Genetics of Liver Disease (GOLD) Consortium; International Consortium for Blood Pressure (ICBP-GWAS); Meta-analyses of Glucose and Insulin-Related Traits Consortium (MAGIC); 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
Collaborators, Affiliations

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

John C Chambers et al. Nat Genet. .

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.

PubMed Disclaimer

Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Summary of study desing
Figure 2
Figure 2
Manhattan plots of association of SNPs with ALT, ALP and GGT in the GWAS. SNPs reaching genome-wide significance (P < 1 × 10−8) are red; SNPs with P > 1 × 10−8 and P < 1 × 10−7 are green.
Figure 3
Figure 3
Association of FADS1, FADS2, GCKR, HNF1A, TRIB1 and PPP1R3B loci with NMR metabonome. Bars are for –log10 P value, signed for direction of effect.
See this image and copyright information in PMC

References

    1. Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med. 2000;342:1266–1271. - PubMed
    1. Söderberg C, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51:595–602. - PubMed
    1. Xu K, et al. Diagnostic value of serum γ-glutamyl transferase isoenzyme for hepatocellular carcinoma: a 10-year study. Am J Gastroenterol. 1992;87:991–995. - PubMed
    1. Sattar N, et al. Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the west of Scotland coronary prevention study. Diabetes. 2004;53:2855–2860. - PubMed
    1. Ioannou GN, Weiss NS, Boyko EJ, Mozaffarian D, Lee SP. Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology. 2006;43:1145–1151. - PubMed

Grants and funding