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, Jeanne Clark

Research output: Contribution to journalArticle

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 (US)
Pages (from-to)1131-1138
Number of pages8
JournalNature Genetics
Volume43
Issue number11
DOIs
StatePublished - Nov 2011

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Genome-Wide Association Study
Liver
Enzymes
Genes
Glycomics
Metabolomics
Membrane Glycoproteins
Carbohydrate Metabolism
Gene Expression Profiling
Lipid Metabolism
Glutathione
Liver Diseases
Immunity
Inflammation
Glucose

ASJC Scopus subject areas

  • Genetics

Cite this

Chambers, J. C., Zhang, W., Sehmi, J., Li, X., Wass, M. N., Van Der Harst, P., ... Clark, J. (2011). Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nature Genetics, 43(11), 1131-1138. https://doi.org/10.1038/ng.970

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

In: Nature Genetics, Vol. 43, No. 11, 11.2011, p. 1131-1138.

Research output: Contribution to journalArticle

Chambers, JC, Zhang, W, Sehmi, J, Li, X, Wass, MN, Van Der Harst, P, Holm, H, Sanna, S, Kavousi, M, Baumeister, SE, Coin, LJ, Deng, G, Gieger, C, Heard-Costa, NL, Hottenga, JJ, Kühnel, B, Kumar, V, Lagou, V, Liang, L, Luan, JA, Vidal, PM, Leach, IM, O'Reilly, PF, Peden, JF, Rahmioglu, N, Soininen, P, Speliotes, EK, Yuan, X, Thorleifsson, G, Alizadeh, BZ, Atwood, LD, Borecki, IB, Brown, MJ, Charoen, P, Cucca, F, Das, D, De Geus, EJC, Dixon, AL, Döring, A, Ehret, G, Eyjolfsson, GI, Farrall, M, Forouhi, NG, Friedrich, N, Goessling, W, Gudbjartsson, DF, Harris, TB, Hartikainen, AL, Heath, S, Hirschfield, GM, Hofman, A, Homuth, G, Hyppönen, E, Janssen, HLA, Johnson, T, Kangas, AJ, Kema, IP, Kühn, JP, Lai, S, Lathrop, M, Lerch, MM, Li, Y, Liang, TJ, Lin, JP, Loos, RJF, Martin, NG, Moffatt, MF, Montgomery, GW, Munroe, PB, Musunuru, K, Nakamura, Y, O'Donnell, CJ, Olafsson, I, Penninx, BW, Pouta, A, Prins, BP, Prokopenko, I, Puls, R, Ruokonen, A, Savolainen, MJ, Schlessinger, D, Schouten, JNL, Seedorf, U, Sen-Chowdhry, S, Siminovitch, KA, Smit, JH, Spector, TD, Tan, W, Teslovich, TM, Tukiainen, T, Uitterlinden, AG, Van Der Klauw, MM, Vasan, RS, Wallace, C, Wallaschofski, H, Wichmann, HE, Willemsen, G, Würtz, P, Xu, C, Yerges-Armstrong, LM, Abecasis, GR, Ahmadi, KR, Boomsma, DI, Caulfield, M, Cookson, WO, Van Duijn, CM, Froguel, P, Matsuda, K, McCarthy, MI, Meisinger, C, Mooser, V, Pietiláinen, KH, Schumann, G, Snieder, H, Sternberg, MJE, Stolk, RP, Thomas, HC, Thorsteinsdottir, U, Uda, M, Waeber, G, Wareham, NJ, Waterworth, DM, Watkins, H, Whitfield, JB, Witteman, JCM, Wolffenbuttel, BHR, Fox, CS, Ala-Korpela, M, Stefansson, K, Vollenweider, P, Völzke, H, Schadt, EE, Scott, J, Járvelin, MR, Elliott, P & Clark, J 2011, 'Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma', Nature Genetics, vol. 43, no. 11, pp. 1131-1138. https://doi.org/10.1038/ng.970
Chambers JC, Zhang W, Sehmi J, Li X, Wass MN, Van Der Harst P et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nature Genetics. 2011 Nov;43(11):1131-1138. https://doi.org/10.1038/ng.970
Chambers, John C. ; Zhang, Weihua ; Sehmi, Joban ; Li, Xinzhong ; Wass, Mark N. ; Van Der Harst, Pim ; Holm, Hilma ; Sanna, Serena ; Kavousi, Maryam ; Baumeister, Sebastian E. ; Coin, Lachlan J. ; Deng, Guohong ; Gieger, Christian ; Heard-Costa, Nancy L. ; Hottenga, Jouke Jan ; Kühnel, Brigitte ; Kumar, Vinod ; Lagou, Vasiliki ; Liang, Liming ; Luan, Jian'An ; Vidal, Pedro Marques ; Leach, Irene Mateo ; O'Reilly, Paul F. ; Peden, John F. ; Rahmioglu, Nilufer ; Soininen, Pasi ; Speliotes, Elizabeth K. ; Yuan, Xin ; Thorleifsson, Gudmar ; Alizadeh, Behrooz Z. ; Atwood, Larry D. ; Borecki, Ingrid B. ; Brown, Morris J. ; Charoen, Pimphen ; Cucca, Francesco ; Das, Debashish ; De Geus, Eco J C ; Dixon, Anna L. ; Döring, Angela ; Ehret, Georg ; Eyjolfsson, Gudmundur I. ; Farrall, Martin ; Forouhi, Nita G. ; Friedrich, Nele ; Goessling, Wolfram ; Gudbjartsson, Daniel F. ; Harris, Tamara B. ; Hartikainen, Anna Liisa ; Heath, Simon ; Hirschfield, Gideon M. ; Hofman, Albert ; Homuth, Georg ; Hyppönen, Elina ; Janssen, Harry L A ; Johnson, Toby ; Kangas, Antti J. ; Kema, Ido P. ; Kühn, Jens P. ; Lai, Sandra ; Lathrop, Mark ; Lerch, Markus M. ; Li, Yun ; Liang, T. Jake ; Lin, Jing Ping ; Loos, Ruth J F ; Martin, Nicholas G. ; Moffatt, Miriam F. ; Montgomery, Grant W. ; Munroe, Patricia B. ; Musunuru, Kiran ; Nakamura, Yusuke ; O'Donnell, Christopher J. ; Olafsson, Isleifur ; Penninx, Brenda W. ; Pouta, Anneli ; Prins, Bram P. ; Prokopenko, Inga ; Puls, Ralf ; Ruokonen, Aimo ; Savolainen, Markku J. ; Schlessinger, David ; Schouten, Jeoffrey N L ; Seedorf, Udo ; Sen-Chowdhry, Srijita ; Siminovitch, Katherine A. ; Smit, Johannes H. ; Spector, Timothy D. ; Tan, Wenting ; Teslovich, Tanya M. ; Tukiainen, Taru ; Uitterlinden, Andre G. ; Van Der Klauw, Melanie M. ; Vasan, Ramachandran S. ; Wallace, Chris ; Wallaschofski, Henri ; Wichmann, H. Erich ; Willemsen, Gonneke ; Würtz, Peter ; Xu, Chun ; Yerges-Armstrong, Laura M. ; Abecasis, Goncalo R. ; Ahmadi, Kourosh R. ; Boomsma, Dorret I. ; Caulfield, Mark ; Cookson, William O. ; Van Duijn, Cornelia M. ; Froguel, Philippe ; Matsuda, Koichi ; McCarthy, Mark I. ; Meisinger, Christa ; Mooser, Vincent ; Pietiláinen, Kirsi H. ; Schumann, Gunter ; Snieder, Harold ; Sternberg, Michael J E ; Stolk, Ronald P. ; Thomas, Howard C. ; Thorsteinsdottir, Unnur ; Uda, Manuela ; Waeber, Gérard ; Wareham, Nicholas J. ; Waterworth, Dawn M. ; Watkins, Hugh ; Whitfield, John B. ; Witteman, Jacqueline C M ; Wolffenbuttel, Bruce H R ; Fox, Caroline S. ; Ala-Korpela, Mika ; Stefansson, Kari ; Vollenweider, Peter ; Völzke, Henry ; Schadt, Eric E. ; Scott, James ; Járvelin, Marjo Riitta ; Elliott, Paul ; Clark, Jeanne. / Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. In: Nature Genetics. 2011 ; Vol. 43, No. 11. pp. 1131-1138.
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title = "Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma",
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.",
author = "Chambers, {John C.} and Weihua Zhang and Joban Sehmi and Xinzhong Li and Wass, {Mark N.} and {Van Der Harst}, Pim and Hilma Holm and Serena Sanna and Maryam Kavousi and Baumeister, {Sebastian E.} and Coin, {Lachlan J.} and Guohong Deng and Christian Gieger and Heard-Costa, {Nancy L.} and Hottenga, {Jouke Jan} and Brigitte K{\"u}hnel and Vinod Kumar and Vasiliki Lagou and Liming Liang and Jian'An Luan and Vidal, {Pedro Marques} and Leach, {Irene Mateo} and O'Reilly, {Paul F.} and Peden, {John F.} and Nilufer Rahmioglu and Pasi Soininen and Speliotes, {Elizabeth K.} and Xin Yuan and Gudmar Thorleifsson and Alizadeh, {Behrooz Z.} and Atwood, {Larry D.} and Borecki, {Ingrid B.} and Brown, {Morris J.} and Pimphen Charoen and Francesco Cucca and Debashish Das and {De Geus}, {Eco J C} and Dixon, {Anna L.} and Angela D{\"o}ring and Georg Ehret and Eyjolfsson, {Gudmundur I.} and Martin Farrall and Forouhi, {Nita G.} and Nele Friedrich and Wolfram Goessling and Gudbjartsson, {Daniel F.} and Harris, {Tamara B.} and Hartikainen, {Anna Liisa} and Simon Heath and Hirschfield, {Gideon M.} and Albert Hofman and Georg Homuth and Elina Hypp{\"o}nen and Janssen, {Harry L A} and Toby Johnson and Kangas, {Antti J.} and Kema, {Ido P.} and K{\"u}hn, {Jens P.} and Sandra Lai and Mark Lathrop and Lerch, {Markus M.} and Yun Li and Liang, {T. Jake} and Lin, {Jing Ping} and Loos, {Ruth J F} and Martin, {Nicholas G.} and Moffatt, {Miriam F.} and Montgomery, {Grant W.} and Munroe, {Patricia B.} and Kiran Musunuru and Yusuke Nakamura and O'Donnell, {Christopher J.} and Isleifur Olafsson and Penninx, {Brenda W.} and Anneli Pouta and Prins, {Bram P.} and Inga Prokopenko and Ralf Puls and Aimo Ruokonen and Savolainen, {Markku J.} and David Schlessinger and Schouten, {Jeoffrey N L} and Udo Seedorf and Srijita Sen-Chowdhry and Siminovitch, {Katherine A.} and Smit, {Johannes H.} and Spector, {Timothy D.} and Wenting Tan and Teslovich, {Tanya M.} and Taru Tukiainen and Uitterlinden, {Andre G.} and {Van Der Klauw}, {Melanie M.} and Vasan, {Ramachandran S.} and Chris Wallace and Henri Wallaschofski and Wichmann, {H. Erich} and Gonneke Willemsen and Peter W{\"u}rtz and Chun Xu and Yerges-Armstrong, {Laura M.} and Abecasis, {Goncalo R.} and Ahmadi, {Kourosh R.} and Boomsma, {Dorret I.} and Mark Caulfield and Cookson, {William O.} and {Van Duijn}, {Cornelia M.} and Philippe Froguel and Koichi Matsuda and McCarthy, {Mark I.} and Christa Meisinger and Vincent Mooser and Pietil{\'a}inen, {Kirsi H.} and Gunter Schumann and Harold Snieder and Sternberg, {Michael J E} and Stolk, {Ronald P.} and Thomas, {Howard C.} and Unnur Thorsteinsdottir and Manuela Uda and G{\'e}rard Waeber and Wareham, {Nicholas J.} and Waterworth, {Dawn M.} and Hugh Watkins and Whitfield, {John B.} and Witteman, {Jacqueline C M} and Wolffenbuttel, {Bruce H R} and Fox, {Caroline S.} and Mika Ala-Korpela and Kari Stefansson and Peter Vollenweider and Henry V{\"o}lzke and Schadt, {Eric E.} and James Scott and J{\'a}rvelin, {Marjo Riitta} and Paul Elliott and Jeanne Clark",
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month = "11",
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TY - JOUR

T1 - Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma

AU - Chambers, John C.

AU - Zhang, Weihua

AU - Sehmi, Joban

AU - Li, Xinzhong

AU - Wass, Mark N.

AU - Van Der Harst, Pim

AU - Holm, Hilma

AU - Sanna, Serena

AU - Kavousi, Maryam

AU - Baumeister, Sebastian E.

AU - Coin, Lachlan J.

AU - Deng, Guohong

AU - Gieger, Christian

AU - Heard-Costa, Nancy L.

AU - Hottenga, Jouke Jan

AU - Kühnel, Brigitte

AU - Kumar, Vinod

AU - Lagou, Vasiliki

AU - Liang, Liming

AU - Luan, Jian'An

AU - Vidal, Pedro Marques

AU - Leach, Irene Mateo

AU - O'Reilly, Paul F.

AU - Peden, John F.

AU - Rahmioglu, Nilufer

AU - Soininen, Pasi

AU - Speliotes, Elizabeth K.

AU - Yuan, Xin

AU - Thorleifsson, Gudmar

AU - Alizadeh, Behrooz Z.

AU - Atwood, Larry D.

AU - Borecki, Ingrid B.

AU - Brown, Morris J.

AU - Charoen, Pimphen

AU - Cucca, Francesco

AU - Das, Debashish

AU - De Geus, Eco J C

AU - Dixon, Anna L.

AU - Döring, Angela

AU - Ehret, Georg

AU - Eyjolfsson, Gudmundur I.

AU - Farrall, Martin

AU - Forouhi, Nita G.

AU - Friedrich, Nele

AU - Goessling, Wolfram

AU - Gudbjartsson, Daniel F.

AU - Harris, Tamara B.

AU - Hartikainen, Anna Liisa

AU - Heath, Simon

AU - Hirschfield, Gideon M.

AU - Hofman, Albert

AU - Homuth, Georg

AU - Hyppönen, Elina

AU - Janssen, Harry L A

AU - Johnson, Toby

AU - Kangas, Antti J.

AU - Kema, Ido P.

AU - Kühn, Jens P.

AU - Lai, Sandra

AU - Lathrop, Mark

AU - Lerch, Markus M.

AU - Li, Yun

AU - Liang, T. Jake

AU - Lin, Jing Ping

AU - Loos, Ruth J F

AU - Martin, Nicholas G.

AU - Moffatt, Miriam F.

AU - Montgomery, Grant W.

AU - Munroe, Patricia B.

AU - Musunuru, Kiran

AU - Nakamura, Yusuke

AU - O'Donnell, Christopher J.

AU - Olafsson, Isleifur

AU - Penninx, Brenda W.

AU - Pouta, Anneli

AU - Prins, Bram P.

AU - Prokopenko, Inga

AU - Puls, Ralf

AU - Ruokonen, Aimo

AU - Savolainen, Markku J.

AU - Schlessinger, David

AU - Schouten, Jeoffrey N L

AU - Seedorf, Udo

AU - Sen-Chowdhry, Srijita

AU - Siminovitch, Katherine A.

AU - Smit, Johannes H.

AU - Spector, Timothy D.

AU - Tan, Wenting

AU - Teslovich, Tanya M.

AU - Tukiainen, Taru

AU - Uitterlinden, Andre G.

AU - Van Der Klauw, Melanie M.

AU - Vasan, Ramachandran S.

AU - Wallace, Chris

AU - Wallaschofski, Henri

AU - Wichmann, H. Erich

AU - Willemsen, Gonneke

AU - Würtz, Peter

AU - Xu, Chun

AU - Yerges-Armstrong, Laura M.

AU - Abecasis, Goncalo R.

AU - Ahmadi, Kourosh R.

AU - Boomsma, Dorret I.

AU - Caulfield, Mark

AU - Cookson, William O.

AU - Van Duijn, Cornelia M.

AU - Froguel, Philippe

AU - Matsuda, Koichi

AU - McCarthy, Mark I.

AU - Meisinger, Christa

AU - Mooser, Vincent

AU - Pietiláinen, Kirsi H.

AU - Schumann, Gunter

AU - Snieder, Harold

AU - Sternberg, Michael J E

AU - Stolk, Ronald P.

AU - Thomas, Howard C.

AU - Thorsteinsdottir, Unnur

AU - Uda, Manuela

AU - Waeber, Gérard

AU - Wareham, Nicholas J.

AU - Waterworth, Dawn M.

AU - Watkins, Hugh

AU - Whitfield, John B.

AU - Witteman, Jacqueline C M

AU - Wolffenbuttel, Bruce H R

AU - Fox, Caroline S.

AU - Ala-Korpela, Mika

AU - Stefansson, Kari

AU - Vollenweider, Peter

AU - Völzke, Henry

AU - Schadt, Eric E.

AU - Scott, James

AU - Járvelin, Marjo Riitta

AU - Elliott, Paul

AU - Clark, Jeanne

PY - 2011/11

Y1 - 2011/11

N2 - 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.

AB - 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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