PubMed ID:
21423719
Public Release Type:
Journal
Publication Year: 2011
Affiliation: Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, United States of America. espeliot@med.umich.edu
DOI:
https://doi.org/10.1371/journal.pgen.1001324
Authors:
Hoofnagle JH,
Florez JC,
Wu J,
Wu J,
Boerwinkle E,
Boerwinkle E,
Liu J,
Vuppalanchi R,
Chalasani N,
Kleiner D,
Abdelmalek M,
Abecasis GR,
Abecasis GR,
Aben KK,
Absher DM,
Alavere H,
Alibrandi MT,
Allen HL,
Almgren P,
Altshuler D,
Amin N,
An P,
Ardlie K,
Ariyurek Y,
Arnold AM,
Aspelund T,
Assimes TL,
Atwood LD,
Aulchenko YS,
Balkau B,
Balkau B,
Balmforth AJ,
Bambha K,
Barlassina C,
Barlow S,
Barroso I,
Barroso I,
Barter P,
Bass NM,
Beckmann JS,
Behling C,
Beilby JP,
Beilby JP,
Belt P,
Benediktsson R,
Bennett AJ,
Bennett AJ,
Ben-Shlomo Y,
Ben-Shlomo Y,
Bergmann S,
Bergmann S,
Bergman RN,
Bergman RN,
Berndt SI,
Bhimalli P,
Biebermann H,
Blakemore AI,
Bochud M,
Boehnke M,
Boehnke M,
Boeing H,
Boes T,
Bonnefond A,
Bonnycastle LL,
Bonnycastle LL,
Boomsma DI,
Boomsma DI,
Borch-Johnsen K,
Borecki IB,
Borecki IB,
Borecki IB,
Borecki IB,
Bornstein SR,
Bornstein SR,
Böttcher Y,
Bouatia-Naji N,
Bouatia-Naji N,
Boyett S,
Brancati F,
Bringman D,
Brown MJ,
Brunner E,
Brunt E,
Bryan D,
Buchanan TA,
Buchanan TA,
Bumpstead SJ,
Busonero F,
Butler JL,
Butler JL,
Campbell H,
Campbell H,
Cao A,
Cappuccio FP,
Carr JJ,
Carr JJ,
Caulfield MJ,
Cavalcanti-Proença C,
Cavalcanti-Proença C,
Chanock SJ,
Charpentier G,
Chasman DI,
Chatterjee N,
Chen CM,
Chen YD,
Chen YD,
Chines P,
Chines PS,
Clarke R,
Clarke R,
Clark J,
Clark JM,
Clark JM,
Clark L,
Coin L,
Coin LJ,
Collins FS,
Collins FS,
Colvin R,
Connell J,
Contos MJ,
Cooper C,
Cooper MN,
Cooper MN,
Cornelis M,
Crawford G,
Crisponi L,
Cummings OW,
Cupples LA,
Dasarathy S,
Day IN,
Day IN,
Dedoussis GV,
de Geus EJ,
Dehghan A,
Deloukas P,
Deloukas P,
Delplanque J,
den Heijer M,
Derdoy J,
Diehl AM,
Dina C,
Dixon AL,
Doney A,
Donithan M,
Doo E,
Duan J,
Dupuis J,
Durelle J,
Ebrahim S,
Ebrahim S,
Edwards K,
Egan JM,
Eiriksdottir G,
Eiriksdottir G,
Eiriksdottir G,
Elliott A,
Elliott P,
Elliott P,
Elosua R,
Erdmann J,
Erdos MR,
Erdos MR,
Eriksson JG,
Esko T,
Estrada K,
Everhart J,
Facheris MF,
Farooqi IS,
Fedson AC,
Feitosa MF,
Feitosa MF,
Feitosa MF,
Felix SB,
Ferreira T,
Ferrell LD,
Ferrucci L,
Filipowski D,
Fischer-Posovszky P,
Fischer-Rosinsky A,
Fisher E,
Folsom AR,
Forouhi NG,
Fox CS,
Fox CS,
Fox CS,
Fox CS,
Franklin CS,
Franks PW,
Frants R,
Franzosi MG,
Frayling TM,
Frayling TM,
Freimer NB,
Friedrich N,
Froguel P,
Froguel P,
Fuchs M,
Fu M,
Gaget S,
Galan P,
Garcia ME,
Garcia ME,
Gejman PV,
Geus EJ,
GIANT Consortium,
Gieger C,
Gieger C,
Gjesing AP,
Glazer NL,
Glazer NL,
Gloyn AL,
Goddard ME,
Goel A,
Goel A,
GOLD Consortium,
Goodarzi MO,
Gottfried M,
Goyette P,
Graessler J,
Graham M,
Grallert H,
Grallert H,
Grarup N,
Grässler J,
Greenawalt DM,
Green M,
Grönberg H,
Groop L,
Groop LC,
Groves CJ,
Groves CJ,
Grundy S,
Gudnason V,
Gudnason V,
Gudnason V,
Guiducci C,
Gustafsson S,
Guy C,
Gwilliam R,
Gyllensten U,
Gyllensten U,
Gyurkey G,
Hadjadj S,
Hall AS,
Hallmans G,
Hall P,
Hammond N,
Hamsten A,
Hansen T,
Hansen T,
Han X,
Haritunians T,
Harris TB,
Harris TB,
Harris TB,
Hartikainen AL,
Hartikainen AL,
Hassanali N,
Hassanali N,
Hassanein T,
Hattersley AT,
Hattersley AT,
Havulinna AS,
Hawkins C,
Hayes RB,
Hayward C,
Hayward C,
Heard-Costa NL,
Heath AC,
Heath SC,
Hebebrand J,
Heid IM,
Heinrich J,
Hengstenberg C,
Henneman P,
Hercberg S,
Herder C,
Hernaez R,
Hernaez R,
Hicks AA,
Hicks AA,
Hillman DR,
Hingorani AD,
Hinney A,
Hirschhorn JN,
Hirschhorn JN,
Hirschhorn JN,
Hoesel V,
Hoffmann J,
Hoffmann U,
Hoffmann U,
Hofman A,
Hofman A,
Homuth G,
Hottenga JJ,
Hottenga JJ,
Hu FB,
Hu FB,
Hui J,
Hui J,
Huikuri HV,
Hung J,
Hunter DJ,
Hveem K,
Hwang SJ,
Hwang SJ,
Igl W,
Illig T,
Illig T,
Ingelsson E,
Ingelsson E,
Iribarren C,
Isaacson M,
Isomaa B,
Isomaa B,
Jackson AU,
Jackson AU,
Jacobs KB,
James AL,
Jansson JO,
Jarick I,
Jarvelin MR,
Jarvelin MR,
Jewell E,
Johansson Å,
Johnson PR,
Johnson T,
Johnson T,
John U,
Jones A,
Jørgensen T,
Jørgensen T,
Jousilahti P,
Jula A,
Jula A,
Kaakinen M,
Kaakinen M,
Kähönen M,
Kajantie E,
Kanoni S,
Kao WH,
Kao WH,
Kao WH,
Kaplan LM,
Kaplan RC,
Kaprio J,
Kaprio J,
Karpe F,
Karpe F,
Kathiresan S,
Kesaniemi YA,
Ketkar S,
Kettunen J,
Khaw KT,
Kiemeney LA,
Killenberg P,
Kilpeläinen TO,
Kim LJ,
Kim LJ,
Kim W,
King D,
Kinnunen L,
Kivimaki M,
Klipsch A,
Knight B,
Knowles JW,
Kolcic I,
Kong A,
König IR,
Koskinen S,
Koskinen S,
Kovacs P,
Kovacs P,
Kowdley KV,
Kraft P,
Krude H,
Kumari M,
Kutalik Z,
Kuusisto J,
Kuusisto J,
Kvaløy K,
Kwan S,
Kyvik KO,
Laakso M,
Laakso M,
Laitinen J,
Lajunen T,
Lamina C,
Langenberg C,
Lantieri O,
Lanzani C,
Lathrop GM,
Launer LJ,
Launer LJ,
Launer LJ,
Lavine JE,
Lawlor DA,
Lawlor DA,
Lawrence RW,
Le Bacquer O,
Lecoeur C,
Lecoeur C,
Lee L,
Lehtimäki T,
Lettre G,
Levinson DF,
Liang L,
Li M,
Lindgren CM,
Lindgren CM,
Lind L,
Li S,
Liu YC,
Li Y,
Lokki ML,
Loos RJ,
Loos RJ,
Lorentzon M,
Luan J,
Luan J,
Luben RN,
Ludwig B,
Luketic VA,
Lyssenko V,
Macciardi F,
MAGIC Investigators,
Mägi R,
Mägi R,
Magnusson PK,
Mahley R,
Mangino M,
Mangino M,
Manning AK,
Manunta P,
Marek D,
Marmot M,
Marre M,
Martínez-Larrad MT,
Martin NG,
Massaro JM,
Massaro JM,
McArdle WL,
McAteer JB,
McCarroll SA,
McCarroll SA,
McCarthy A,
McCarthy MI,
McCarthy MI,
McCulloch LJ,
McCullough A,
McKnight B,
McPherson R,
Meigs JB,
Meisinger C,
Meitinger T,
Melander O,
Melzer D,
Meneton P,
Merriman R,
Metspalu A,
Meyre D,
Meyre D,
Midthjell K,
Miriel L,
Mitchell BD,
Mitchell BD,
Mitchell BD,
Moffatt MF,
Mohlke KL,
Mohlke KL,
Molleston J,
Monda KL,
Montgomery GW,
Mooney J,
Mooser V,
Morken MA,
Morken MA,
Morris AD,
Morris AP,
Morris AP,
Mukherjee S,
Mulic R,
Munroe PB,
Myers RH,
Naitza S,
Nalls MA,
Nalls MA,
Narisu N,
Narisu N,
NASH CRN,
Nathan DM,
Navarro P,
Nelis M,
Nelson J,
Nemesh J,
Neuschwander-Tetri BA,
Neville MJ,
Neville MJ,
Ngwa JS,
Nieminen MS,
North KE,
Nyholt DR,
O'Connell J,
O'Connell JR,
O'Donnell CJ,
O'Donnell CJ,
O'Donnell CJ,
Ohlsson C,
Ong KK,
Oostra B,
Oostra BA,
O'Rahilly S,
Orrù M,
Ouwehand WH,
Pabst M,
Pakyz R,
Palmer CD,
Palmer CD,
Palmer CN,
Palmer LJ,
Palmer LJ,
Pankow JS,
Pan YP,
Paolisso G,
Paré G,
Parker AN,
Park JH,
Pattaro C,
Pattou F,
Payne F,
Pearson D,
Peden JF,
Pedersen NL,
Pedersen O,
Pedersen O,
Pellikka N,
Peltonen L,
Peltonen L,
Penninx BW,
Penninx BW,
Perola M,
Perola M,
Perry JR,
Perry JR,
Petcharaporn L,
Peters A,
Peters MJ,
Pfeiffer AF,
Pichler I,
Pichler I,
Piercy D,
Pietiläinen KH,
Platou CG,
Polasek O,
Polasek O,
Posthuma D,
Potter SC,
Pouta A,
Pouta A,
Pramstaller PP,
Pramstaller PP,
Preuss M,
Prokopenko I,
Prokopenko I,
Province MA,
Psaty BM,
Purcell S,
Qi L,
Qi L,
Quertermous T,
Rafelt S,
Ragozzino L,
Raitakari O,
Randall J,
Randall JC,
Rathmann W,
Raychaudhuri S,
Rayner NW,
Rayner NW,
Reinehr T,
Rice K,
Ridderstråle M,
Ridker PM,
Rief W,
Ripatti S,
Ripatti S,
Rissanen A,
Rivadeneira F,
Rivadeneira F,
Robertson NR,
Roberts S,
Robuck PR,
Roccasecca RM,
Rocheleau G,
Roden M,
Rogers N,
Rolandsson O,
Rosenthal M,
Rosenthal P,
Rotter JI,
Rudan I,
Rudan I,
Ruokonen A,
Ruokonen A,
Rybin D,
Rzehak P,
Sahani DV,
Sahani DV,
Salomaa V,
Salomaa V,
Salomaa V,
Samani NJ,
Sampson MJ,
Sandbaek A,
Sanders AR,
Sandholt C,
Sandhu B,
Sandhu M,
Sandhu MS,
Sanna S,
Sanna S,
Sanyal AJ,
Saramies J,
Sargeant C,
Sargent R,
Saunders C,
Savolainen MJ,
Saxena R,
Sayer AA,
Schadt EE,
Schadt EE,
Scheet P,
Scherag A,
Scherag S,
Schipf S,
Schlessinger D,
Schlessinger D,
Schreiber S,
Schunkert H,
Schwartz SM,
Schwarz P,
Schwarz PE,
Schwimmer JB,
Scott LJ,
Scott LJ,
Scuteri A,
Seedorf U,
Seeff L,
Segrè AV,
Selph K,
Serrano-Ríos M,
Sethupathy P,
Sharp SJ,
Shields B,
Shi J,
Shrader P,
Shuldiner AR,
Shuldiner AR,
Shuldiner AR,
Shuldiner AR,
Siegner J,
Sigurðsson G,
Sijbrands EJ,
Silander K,
Silander K,
Silveira A,
Simpson L,
Singleton A,
Sinisalo J,
Sirlin C,
Siscovick DS,
Siscovick DS,
Siscovick DS,
Sladek R,
Smith AV,
Smith AV,
Smith AV,
Smith GD,
Smith GD,
Smith M,
Smith NL,
Smit JH,
Song K,
Soranzo N,
Soranzo N,
Sovio U,
Sovio U,
Sparsø T,
Spector TD,
Spector TD,
Speliotes EK,
Speliotes EK,
Speliotes EK,
Spranger J,
Stager M,
Stead A,
Steel T,
Stefansson K,
Stefansson K,
Stein T,
Steinthorsdottir V,
Steinthorsdottir V,
Stephens J,
Sternberg A,
Stewart S,
Strachan DP,
Stringham HM,
Stringham HM,
Stumvoll M,
Stumvoll M,
Surakka I,
Swift A,
Swift AJ,
Syddall H,
Syvänen AC,
Tammesoo ML,
Tanaka T,
Tardif JC,
Teder-Laving M,
Teslovich TM,
Thiering E,
Thompson J,
Thompson JR,
Thomson B,
Thorand B,
Thorleifsson G,
Thorleifsson G,
Thorsteinsdottir U,
Thorsteinsdottir U,
Tichet J,
Timpson NJ,
Timpson NJ,
Tomas M,
Tonascia J,
Tönjes A,
Tönjes A,
Tuomilehto J,
Tuomilehto J,
Tuomi T,
Tuomi T,
Tyrer JP,
Uda M,
Uda M,
Uitterlinden A,
Uitterlinden AG,
Ünalp A,
Valle TT,
Valle TT,
van Dijk KW,
van Duijn CM,
van Duijn CM,
van Hoek M,
van Meurs JB,
Van Natta M,
van Ommen GJ,
van Wingerden S,
Varma D,
Vatin V,
Vedantam S,
Viikari J,
Visscher PM,
Visvikis-Siest S,
Visvikis-Siest S,
Vitart V,
Vitart V,
Vogel CI,
Vogelzangs N,
Voight BF,
Voight BF,
Voight BF,
Vollenweider P,
Wabitsch M,
Waeber G,
Waeber G,
Wagner PJ,
Waite LL,
Wallaschofski H,
Walley A,
Walters GB,
Walters GB,
Wang C,
Ward KL,
Wareham NJ,
Wareham NJ,
Watanabe RM,
Watanabe RM,
Waterworth DM,
Watkins H,
Watkins H,
Weedon MN,
Weedon MN,
Welch R,
Weyant RJ,
Wheeler E,
Wheeler E,
White CC,
White M,
Wichmann HE,
Wichmann HE,
Widen E,
Wiegand S,
Wiklund F,
Wild SH,
Wild SH,
Willemsen G,
Willemsen G,
Willer CJ,
Williams GH,
Wilson JF,
Wilson JF,
Wilson L,
Winkler TW,
Witte DR,
Witteman JC,
Witteman JC,
Wood AR,
Workalemahu T,
Wright AF,
Wright AF,
Xu J,
Yang J,
Yarnell JW,
Yates K,
Yeh M,
Yerges-Armstrong LM,
Yerges-Armstrong LM,
Zabena C,
Zeggini E,
Zelenika D,
Zethelius B,
Zgaga L,
Zhai G,
Zhang Q,
Zhao JH,
Zhao JH,
Ziegler A,
Zillikens MC,
Zillikens MC,
Zitting P
Studies:
Nonalcoholic Steatohepatitis Clinical Research Network
Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.