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.
Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits / Speliotes, Elizabeth K; Yerges-Armstrong, Laura M; Wu, Jun; Hernaez, Ruben; Kim, Lauren J; Palmer, Cameron D; Gudnason, Vilmundur; Eiriksdottir, Gudny; Garcia, Melissa E; Launer, Lenore J; Nalls, Michael A; Clark, Jeanne M; Mitchell, Braxton D; Shuldiner, Alan R; Butler, Johannah L; Tomas, Marta; Hoffmann, Udo; Hwang, Shih-Jen; Massaro, Joseph M; O'Donnell, Christopher J.; Sahani, Dushyant V; Salomaa, Veikko; Schadt, Eric E; Schwartz, Stephen M; Siscovick, David S; Voight, Benjamin F; Jeffrey Carr, J.; Feitosa, Mary F; Harris, Tamara B; Fox, Caroline S; Smith, Albert V; Linda Kao, W. H.; Hirschhorn, Joel N; Borecki, Ingrid B; Mccullough, Arthur; Bringman, Diane; Dasarathy, Srinivasan; Edwards, Kevin; Hawkins, Carol; Liu, Yao-Chang; Rogers, Nicholette; Ruth Sargent, P. A. -C.; Stager, Margaret; Diehl, Anna Mae; Abdelmalek, Manal; Gottfried, Marcia; Guy, Cynthia; Killenberg, Paul; Kwan, Samantha; Pan, Yi-Ping; Piercy, Dawn; Smith, Melissa; Chalasani, Naga; Bhimalli, Prajakta; Cummings, Oscar W.; Klipsch, Ann; Lee, Lydia; Molleston, Jean; Ragozzino, Linda; Vuppalanchi, Raj; Neuschwander-Tetri, Brent A.; Barlow, Sarah; Derdoy, Jose; Hoffmann, Joyce; King, Debra; Siegner, Joan; Stewart, Susan; Thompson, Judy; Brunt, Elizabeth; Lavine, Joel E.; Behling, Cynthia; Clark, Lisa; Durelle, Janis; Hassanein, Tarek; Petcharaporn, Lita; Schwimmer, Jeffrey B.; Sirlin, Claude; Stein, Tanya; Bass, Nathan M.; Bambha, Kiran; Ferrell, Linda D.; Filipowski, Danuta; Merriman, Raphael; Pabst, Mark; Rosenthal, Monique; Rosenthal, Philip; Steel, Tessa; Sanyal, Arun J.; Boyett, Sherry; Bryan, Daphne; Contos, Melissa J.; Fuchs, Michael; Graham, Martin; Jones, Amy; Luketic, Velimir A. C.; Sandhu, Bimalijit; Sargeant, Carol; Selph, Kimberly; White, Melanie; Kowdley, Kris V.; Gyurkey, Grace; Mooney, Jody; Nelson, James; Roberts, Sarah; Saunders, Cheryl; Stead, Alice; Wang, Chia; Yeh, Matthew; Kleiner, David; Doo, Edward; Everhart, Jay; Hoofnagle, Jay H.; Robuck, Patricia R.; Seeff, Leonard; Tonascia, James; Belt, Patricia; Brancati, Fred; Colvin, Ryan; Donithan, Michele; Green, Mika; Isaacson, Milana; Kim, Wana; Miriel, Laura; Sternberg, Alice; Ünalp, Aynur; Van Natta, Mark; Wilson, Laura; Yates, Katherine; Willer, Cristen J.; Berndt, Sonja I.; Monda, Keri L.; Thorleifsson, Gudmar; Jackson, Anne U.; Allen, Hana Lango; Lindgren, Cecilia M.; Luan, Jian'An; Mägi, Reedik; Randall, Joshua; Vedantam, Sailaja; Winkler, Thomas W.; Qi, Lu; Workalemahu, Tsegaselassie; Heid, Iris M.; Steinthorsdottir, Valgerdur; Stringham, Heather M.; Weedon, Michael N.; Wheeler, Eleanor; Wood, Andrew R.; Ferreira, Teresa; Weyant, Robert J.; Segrè, Ayellet V.; Estrada, Karol; Liang, Liming; Nemesh, James; Park, Ju-Hyun; Gustafsson, Stefan; Kilpeläinen, Tuomas O.; Yang, Jian; Bouatia-Naji, Nabila; Esko, Tõnu; Kutalik, Zoltán; Mangino, Massimo; Raychaudhuri, Soumya; Scherag, Andre; Welch, Ryan; Zhao, Jing Hua; Aben, Katja K.; Absher, Devin M.; Amin, Najaf; Dixon, Anna L.; Fisher, Eva; Glazer, Nicole L.; Goddard, Michael E.; Heard-Costa, Nancy L.; Hoesel, Volker; Hottenga, Jouke Jan; Johansson, Åsa; Johnson, Toby; Ketkar, Shamika; Lamina, Claudia; Li, Shengxu; Moffatt, Miriam F.; Myers, Richard H.; Narisu, Narisu; Perry, John R. B.; Peters, Marjolein J.; Preuss, Michael; Ripatti, Samuli; Rivadeneira, Fernando; Sandholt, Camilla; Scott, Laura J.; Timpson, Nicholas J.; Tyrer, Jonathan P.; van Wingerden, Sophie; Watanabe, Richard M.; White, Charles C.; Wiklund, Fredrik; Barlassina, Christina; Chasman, Daniel I.; Cooper, Matthew N.; Jansson, John-Olov; Lawrence, Robert W.; Pellikka, Niina; Prokopenko, Inga; Shi, Jianxin; Thiering, Elisabeth; Alavere, Helene; Alibrandi, Maria T. S.; Almgren, Peter; Arnold, Alice M.; Aspelund, Thor; Atwood, Larry D.; Balkau, Beverley; Balmforth, Anthony J.; Bennett, Amanda J.; Ben-Shlomo, Yoav; Bergman, Richard N.; Bergmann, Sven; Biebermann, Heike; Blakemore, Alexandra I. F.; Boes, Tanja; Bonnycastle, Lori L.; Bornstein, Stefan R.; Brown, Morris J.; Buchanan, Thomas A.; Busonero, Fabio; Campbell, Harry; Cappuccio, Francesco P.; Cavalcanti-Proença, Christine; Chen, Yii-Der Ida; Chen, Chih-Mei; Chines, Peter; Clarke, Robert; Coin, Lachlan J. M.; Connell, John; Day, Ian N. M.; den Heijer, Martin; Duan, Jubao; Ebrahim, Shah; Elliott, Paul; Elosua, Roberto; Erdos, Michael R.; Eriksson, Johan G.; Facheris, Maurizio F.; Felix, Stephan B.; Fischer-Posovszky, Pamela; Folsom, Aaron R.; Friedrich, Nele; Freimer, Nelson B.; Fu, Mao; Gaget, Stefan; Gejman, Pablo V.; Geus, Eco J. C.; Gieger, Christian; Gjesing, Anette P.; Goel, Anuj; Goyette, Philippe; Grallert, Harald; Gräβler, Jürgen; Greenawalt, Danielle M.; Groves, Christopher J.; Guiducci, Candace; Hartikainen, Anna-Liisa; Hassanali, Neelam; Hall, Alistair S.; Havulinna, Aki S.; Hayward, Caroline; Heath, Andrew C.; Hengstenberg, Christian; Hicks, Andrew A.; Hinney, Anke; Hofman, Albert; Homuth, Georg; Hui, Jennie; Igl, Wilmar; Iribarren, Carlos; Isomaa, Bo; Jacobs, Kevin B.; Jarick, Ivonne; Jewell, Elizabeth; John, Ulrich; Jørgensen, Torben; Jousilahti, Pekka; Jula, Antti; Kaakinen, Marika; Kajantie, Eero; Kaplan, Lee M.; Kathiresan, Sekar; Kettunen, Johannes; Kinnunen, Leena; Knowles, Joshua W.; Kolcic, Ivana; König, Inke R.; Koskinen, Seppo; Kovacs, Peter; Kuusisto, Johanna; Kraft, Peter; Kvaløy, Kirsti; Laitinen, Jaana; Lantieri, Olivier; Lanzani, Chiara; Lecoeur, Cecile; Lehtimäki, Terho; Lettre, Guillaume; Liu, Jianjun; Lokki, Marja-Liisa; Lorentzon, Mattias; Luben, Robert N.; Ludwig, Barbara; Manunta, Paolo; Marek, Diana; Marre, Michel; Martin, Nicholas G.; Mcardle, Wendy L.; Mccarthy, Anne; Mcknight, Barbara; Meitinger, Thomas; Melander, Olle; Meyre, David; Midthjell, Kristian; Montgomery, Grant W.; Morken, Mario A.; Morris, Andrew P.; Mulic, Rosanda; Ngwa, Julius S.; Nelis, Mari; Neville, Matt J.; Nyholt, Dale R.; O'Rahilly, Stephen; Ong, Ken K.; Oostra, Ben; Paré, Guillaume; Parker, Alex N.; Perola, Markus; Pichler, Irene; Pietiläinen, Kirsi H.; Platou, Carl G. P.; Polasek, Ozren; Pouta, Anneli; Rafelt, Suzanne; Raitakari, Olli; Rayner, Nigel W.; Ridderstråle, Martin; Rief, Winfried; Ruokonen, Aimo; Robertson, Neil R.; Rzehak, Peter; Sanders, Alan R.; Sandhu, Manjinder S.; Sanna, Serena; Saramies, Jouko; Savolainen, Markku J.; Scherag, Susann; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Silander, Kaisa; Sinisalo, Juha; Smit, Jan H.; Soranzo, Nicole; Sovio, Ulla; Stephens, Jonathan; Surakka, Ida; Swift, Amy; Tammesoo, Mari-Liis; Tardif, Jean-Claude; Teder-Laving, Maris; Teslovich, Tanya M.; Thompson, John R.; Thomson, Brian; Tönjes, Anke; Tuomi, Tiinamaija; van Meurs, Joyce B. J.; van Ommen, Gert-Jan; Vatin, Vincent; Viikari, Jorma; Visvikis-Siest, Sophie; Vitart, Veronique; Vogel, Carla I. G.; Waite, Lindsay L.; Wallaschofski, Henri; Bragi Walters, G.; Widen, Elisabeth; Wiegand, Susanna; Wild, Sarah H.; Willemsen, Gonneke; Witte, Daniel R.; Witteman, Jacqueline C.; Xu, Jianfeng; Zhang, Qunyuan; Zgaga, Lina; Ziegler, Andreas; Zitting, Paavo; Beilby, John P.; Farooqi, I. Sadaf; Hebebrand, Johannes; Huikuri, Heikki V.; James, Alan L.; Kähönen, Mika; Levinson, Douglas F.; Macciardi, Fabio; Nieminen, Markku S.; Ohlsson, Claes; Ridker, Paul M.; Stumvoll, Michael; Beckmann, Jacques S.; Boeing, Heiner; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Chanock, Stephen J.; Adrienne Cupples, L.; Smith, George Davey; Erdmann, Jeanette; Froguel, Philippe; Grönberg, Henrik; Gyllensten, Ulf; Hall, Per; Hansen, Torben; Hattersley, Andrew T.; Hayes, Richard B.; Heinrich, Joachim; Hu, Frank B.; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Kaprio, Jaakko; Karpe, Fredrik; Khaw, Kay-Tee; Kiemeney, Lambertus A.; Krude, Heiko; Laakso, Markku; Lawlor, Debbie A.; Metspalu, Andres; Munroe, Patricia B.; Ouwehand, Willem H.; Pedersen, Oluf; Penninx, Brenda W.; Peters, Annette; Pramstaller, Peter P.; Quertermous, Thomas; Reinehr, Thomas; Rissanen, Aila; Rudan, Igor; Samani, Nilesh J.; Schwarz, Peter; Spector, Timothy D.; Tuomilehto, Jaakko; Uda, Manuela; Uitterlinden, André G.; Valle, Timo T.; Wabitsch, Martin; Waeber, Gérard; Wareham, Nicholas J.; Watkins, Hugh; Wilson, James F.; Wright, Alan F.; Carola Zillikens, M.; Chatterjee, Nilanjan; Mc, Steven A.; Purcell, Shaun; Visscher, Peter M.; Assimes, Themistocles L.; Deloukas, Panos; Groop, Leif C.; Haritunians, Talin; Hunter, David J.; Kaplan, Robert C.; Mohlke, Karen L.; O'Connell, Jeffrey R.; Peltonen, Leena; Schlessinger, David; Strachan, David P.; van Duijn, Cornelia M.; Wichmann, H. -Erich; Frayling, Timothy M.; Thorsteinsdottir, Unnur; Abecasis, Gonçalo R.; Barroso, Inês; Boehnke, Michael; Stefansson, Kari; North, Kari E.; Mccarthy, Mark I.; Ingelsson, Erik; Loos, Ruth J. F.; Dupuis, Josée; Langenberg, Claudia; Saxena, Richa; Gloyn, Anna L.; Rybin, Denis; Henneman, Peter; Dehghan, Abbas; Franklin, Christopher S; Navarro, Pau; Song, Kijoung; Egan, Josephine M; Lajunen, Taina; Grarup, Niels; Sparsø, Thomas; Doney, Alex; Li, Man; Kanoni, Stavroula; Shrader, Peter; Kumari, Meena; Zabena, Carina; Rocheleau, Ghislain; An, Ping; Elliott, Amanda; Mccarroll, Steven A; Payne, Felicity; Roccasecca, Rosa Maria; Pattou, François; Sethupathy, Praveen; Ardlie, Kristin; Ariyurek, Yavuz; Barter, Philip; Benediktsson, Rafn; Bochud, Murielle; Bonnefond, Amélie; Borch-Johnsen, Knut; Böttcher, Yvonne; Brunner, Eric; Bumpstead, Suzannah J; Charpentier, Guillaume; Cornelis, Marilyn; Crawford, Gabe; Crisponi, Laura; de Geus, Eco J. C.; Delplanque, Jerome; Dina, Christian; Fedson, Annette C; Fischer-Rosinsky, Antje; Forouhi, Nita G; Frants, Rune; Franzosi, Maria Grazia; Galan, Pilar; Goodarzi, Mark O; Graessler, Jürgen; Grundy, Scott; Gwilliam, Rhian; Hadjadj, Samy; Hallmans, Göran; Hammond, Naomi; Han, Xijing; Heath, Simon C.; Hercberg, Serge; Herder, Christian; Hillman, David R.; Hingorani, Aroon D.; Hung, Joe; Johnson, Paul R. V.; Antero Kesaniemi, Y.; Kivimaki, Mika; Knight, Beatrice; Kyvik, Kirsten Ohm; Lathrop, G. Mark; Bacquer, Olivier Le; Li, Yun; Lyssenko, Valeriya; Mahley, Robert; Manning, Alisa K.; Martínez-Larrad, María Teresa; Mcateer, Jarred B.; Mcculloch, Laura J.; Mcpherson, Ruth; Meisinger, Christa; Melzer, David; Mukherjee, Sutapa; Naitza, Silvia; Orrù, Marco; Pakyz, Ruth; Palmer, Colin N. A.; Paolisso, Giuseppe; Pattaro, Cristian; Pearson, Daniel; Peden, John F.; Pedersen, Nancy L.; Pfeiffer, Andreas F. H.; Posthuma, Danielle; Potter, Simon C.; Province, Michael A.; Psaty, Bruce M.; Rathmann, Wolfgang; Rice, Kenneth; Roden, Michael; Rolandsson, Olov; Sandbaek, Annelli; Sayer, Avan Aihie; Scheet, Paul; Seedorf, Udo; Sharp, Stephen J.; Shields, Beverley; Sigurðsson, Gunnar; Sijbrands, Eric J. G.; Silveira, Angela; Simpson, Laila; Singleton, Andrew; Smith, Nicholas L.; Syddall, Holly; Syvänen, Ann-Christine; Tanaka, Toshiko; Thorand, Barbara; Tichet, Jean; van Dijk, Ko Willems; van Hoek, Mandy; Varma, Dhiraj; Vogelzangs, Nicole; Wagner, Peter J; Walley, Andrew; Walters, G. Bragi; Ward, Kim L.; Witteman, Jaqueline C. M.; Yarnell, John W. G.; Zeggini, Eleftheria; Zelenika, Diana; Zethelius, Björn; Zhai, Guangju; Zillikens, M Carola; Meneton, Pierre; Magnusson, Patrik K. E.; Nathan, David M.; Williams, Gordon H.; Spranger, Joachim; Cooper, Cyrus; Dedoussis, George V.; Lind, Lars; Morris, Andrew D.; Palmer, Lyle J.; Franks, Paul W.; Marmot, Michael; Pankow, James S.; Sampson, Michael J.; Erich Wichmann, H.; Hamsten, Anders; Altshuler, David; Rotter, Jerome I.; Ferrucci, Luigi; Kong, Augustine; Duijn, Cornelia Mvan; Aulchenko, Yurii S.; Cao, Antonio; Scuteri, Angelo; Waterworth, Dawn M; Vollenweider, Peter; Mooser, Vincent; Sladek, Robert; Meigs, James B; Florez, Jose C. - In: PLOS GENETICS. - ISSN 1553-7390. - 7:3(2011), p. e1001324. [10.1371/journal.pgen.1001324]
Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits
Scuteri, AngeloMembro del Collaboration Group
;
2011-01-01
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
