Author: "Dawn M. Waterworth" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Dawn M. Waterworth"' showing total 128 results

Start Over Author "Dawn M. Waterworth"

128 results on '"Dawn M. Waterworth"'

101. We-P11:81 Association of insulin resistance with increased plasma transaminases levels in a Swiss population/the CoLaus study

Author: Dawn M. Waterworth, Kijoung Song, V. Mayor, Gérard Waeber, Peter Vollenweider, F. Paccaud, Vincent Mooser, and M. Firmann
Subjects: medicine.medical_specialty, education.field_of_study, business.industry, Population, General Medicine, medicine.disease, Endocrinology, Insulin resistance, Internal medicine, Internal Medicine, Medicine, Cardiology and Cardiovascular Medicine, business, education
Published: 2006

102. Genetic Polymorphisms of the Main Transcription Factors for Adiponectin Gene Promoter in Regulation of Adiponectin Levels: Association Analysis in Three European Cohorts

Author: Tobias Kiesslich, Iris M. Heid, Claudia Lamina, Dawn M. Waterworth, Sven Bergmann, Karen Kapur, Igor Kedenko, Lyudmyla Kedenko, H.-Erich Wichmann, Florian Kronenberg, and Bernhard Paulweber
Subjects: Male, Epidemiology, lcsh:Medicine, Biochemistry, Linkage Disequilibrium, Cohort Studies, 0302 clinical medicine, Enhancer binding, lcsh:Science, Promoter Regions, Genetic, 2. Zero hunger, Genetics, 0303 health sciences, Multidisciplinary, Middle Aged, 3. Good health, Medicine, Female, Adiponectin, hormones, hormone substitutes, and hormone antagonists, Research Article, Adult, Clinical Research Design, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Genetic variation, Genetic model, Humans, Genetic Association Studies, Aged, 030304 developmental biology, Genetic association, Clinical Genetics, Population Biology, lcsh:R, Haplotype, Proteins, Human Genetics, Promoter, Regulatory Proteins, Metabolism, Metabolic Disorders, Genetic Polymorphism, Linear Models, lcsh:Q, Population Genetics, Transcription Factors
Abstract: Adiponectin serum concentrations are an important biomarker in cardiovascular epidemiology with heritability etimates of 30-70%. However, known genetic variants in the adiponectin gene locus (ADIPOQ) account for only 2%-8% of its variance. As transcription factors are thought to play an under-acknowledged role in carrying functional variants, we hypothesized that genetic polymorphisms in genes coding for the main transcription factors for the ADIPOQ promoter influence adiponectin levels. Single nucleotide polymorphisms (SNPs) at these genes were selected based on the haplotype block structure and previously published evidence to be associated with adiponectin levels. We performed association analyses of the 24 selected SNPs at forkhead box O1 (FOXO1), sterol-regulatory-element-binding transcription factor 1 (SREBF1), sirtuin 1 (SIRT1), peroxisome-proliferator-activated receptor gamma (PPARG) and transcription factor activating enhancer binding protein 2 beta (TFAP2B) gene loci with adiponectin levels in three different European cohorts: SAPHIR (n = 1742), KORA F3 (n = 1636) and CoLaus (n = 5355). In each study population, the association of SNPs with adiponectin levels on log-scale was tested using linear regression adjusted for age, sex and body mass index, applying both an additive and a recessive genetic model. A pooled effect size was obtained by meta-analysis assuming a fixed effects model. We applied a significance threshold of 0.0033 accounting for the multiple testing situation. A significant association was only found for variants within SREBF1 applying an additive genetic model (smallest p-value for rs1889018 on log(adiponectin) = 0.002, β on original scale = -0.217 µg/ml), explaining ∼0.4% of variation of adiponectin levels. Recessive genetic models or haplotype analyses of the FOXO1, SREBF1, SIRT1, TFAPB2B genes or sex-stratified analyses did not reveal additional information on the regulation of adiponectin levels. The role of genetic variations at the SREBF1 gene in regulating adiponectin needs further investigation by functional studies.
Published: 2012

103. Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals

Author: Seppo Koskinen, Christian Herder, Daniel I. Chasman, Andrew R. Wood, Jonna L. Grimsby, J.F. Wilson, Day Inm., Massimo Mangino, Gonneke Willemsen, Robert W. Mahley, Cristian Pattaro, Nicole L. Glazer, T.B. Harris, Irene Pichler, M S Sandhu, D. van Heemst, Christine Proença, Martha Ganser, Robert A. Hegele, Richa Saxena, Eleftheria Zeggini, Markku Laakso, Peter Kraft, Judith B. Borja, Karen L. Mohlke, J B Richards, de Geus Ejc., Robert Sladek, Cristen J. Willer, Samy Hadjadj, S.M. Boekholdt, Gina M. Peloso, Kijoung Song, Sutapa Mukherjee, Gudmar Thorleifsson, Winston Hide, Mark I. McCarthy, Ruth E. Pakyz, Marian Beekman, Ayellet V. Segrè, Inga Prokopenko, Ping An, George Dedoussis, Danielle Posthuma, Jeanette Erdmann, Simon J. Griffin, Nilesh J. Samani, Inke R. König, Frank B. Hu, Lokki M-L., David M. Evans, Xiaohui Li, Valgerdur Steinthorsdottir, Aimo Ruokonen, A Pouta, Kerrin S. Small, Cecilia M. Lindgren, O Le Bacquer, Xijing Han, Florian Kronenberg, E Katsareli, Christian Dina, S. Gabriel, Jochen Spranger, James S. Pankow, M. Kloppenburg, Penninx Bwjh., Torben Hansen, Josh Smith, Jennie Hui, Gordon H. Williams, Mark Seielstad, Ingrid B. Borecki, Weihua Zhang, Peter P. Pramstaller, Stephen J. Sharp, Neil R. Robertson, Zee Ryl., Mike Sampson, Angela Silveira, C.M. van Duijn, Anders Hamsten, Peter Shrader, Denis Rybin, Chen Y-Di., Gunnar Sigurdsson, Michael Stumvoll, Russel Tracy, Mark O. Goodarzi, Göran Hallmans, Michael R. Erdos, Valeriya Lyssenko, Juha Saharinen, Sven Bergmann, Jeffrey R. O'Connell, Debbie A Lawlor, Thomas Meitinger, Yvonne Böttcher, Jérôme Delplanque, Sarah G. Buxbaum, Silvia Naitza, Shah Ebrahim, Graham A. Hitman, Angelo Scuteri, Aroon D. Hingorani, Heribert Schunkert, François Pattou, Claudia Lamina, A L Elliott, Sekar Kathiresan, Dawn M. Waterworth, Jennifer A. Brody, Thomas Quertermous, Leena Peltonen, Josephine M. Egan, Daniel J. Rader, J F Peden, Yarnell Jwg., Daniel S. Pearson, Pfeiffer Afh., P S Chines, N Vogelzangs, Susan Redline, Alka M. Kanaya, T B Harris, J. V. van Vliet-Ostaptchouk, Ghislain Rocheleau, Rune R. Frants, Olga D. Carlson, James G. Wilson, Melissa Garcia, Ong Rt-H., Mark J. Caulfield, Tanya M. Teslovich, Loo B-M., Beatrice Knight, Andreas Ziegler, Claudia Langenberg, Yoon Shin Cho, Paul M. Ridker, Mark J. Rieder, Praveen Sethupathy, Bert Bravenboer, J. Viikari, Matt Neville, Ioannis M. Stylianou, Andrew Walley, Jarvelin M-R., Jarred B. McAteer, Ronald M. Krauss, Augustine Kong, Oluf Pedersen, Mark J. Daly, Andrew P. Morris, Anna F. Dominiczak, Stéphane Cauchi, Michael Boehnke, Christopher J. O'Donnell, Barbara Thorand, Peter M. Nilsson, Aaron Isaacs, Deborah A. Nickerson, Roza Blagieva, Mary F. Feitosa, Nicholas J. Wareham, Robert Roberts, J S Kooner, K W van Dijk, Tiinamaija Tuomi, Paul Scheet, Lynda M. Rose, Albert V. Smith, Rafn Benediktsson, Chiara Sabatti, Candace Guiducci, Lee M. Kaplan, Aki S. Havulinna, Toby Johnson, Samuli Ripatti, Erik Ingelsson, Mario A. Morken, Carl G. P. Platou, Anke Tönjes, Qi Sun, Narisu Narisu, S J Bumpstead, Jose M. Ordovas, Alan B. Feranil, L Groop, P Chines, Sara M. Willems, Perry Jrb., Matthew A. Allison, Jan Scott, Cécile Lecoeur, Kastelein Jjp., Herman A. Taylor, Anyuan Cao, Christopher J. Groves, Lincoln D. Stein, Laura J. Scott, John Beilby, Kristin G. Ardlie, Christopher S. Franklin, Yoav Ben-Shlomo, B M Shields, N J Timpson, Marco Orrù, Amélie Bonnefond, Kiran Musunuru, Murielle Bochud, Udo Seedorf, Yongmei Liu, Guillaume Lettre, Lee J-Y., Alan R. Shuldiner, Ryan P. Welch, David J. Hunter, John Whitfield, Klaus Strassburger, Khaw K-T., Hartikainen A-L., Gunnar Sigurðsson, Lu Qi, Richard N. Bergman, G M Lathrop, Sigrid W. Fouchier, T van Herpt, David S. Siscovick, Igor Rudan, Richard M. Watanabe, Themistocles L. Assimes, Nicholas G. Martin, Ozren Polasek, Dhiraj Varma, K Kim, Oliver Hofmann, Nicholas D. Hastie, S Bumpstead, Jose C. Florez, Fernando Rivadeneira, Katharine R. Owen, Braxton D. Mitchell, Alisa K. Manning, Abbas Dehghan, Bruce Bartholow Duncan, Cisca Wijmenga, Timo T. Valle, Jaakko Kaprio, Mika Kivimäki, B Shields, Laila Simpson, Tim D. Spector, Paul W. Franks, Guangju Zhai, María Teresa Martínez-Larrad, Janssens Acjw., Kim L. Ward, Inês Barroso, Xiuqing Guo, Rosa Maria Roccasecca, Zari Dastani, Reijo Laaksonen, Wilmar Igl, Vincent Mooser, Niels Grarup, Cornelia Huth, Christian Gieger, Fabio Marroni, Jaakko Tuomilehto, Doney Asf., Andrew C. Edmondson, Christian Fuchsberger, Meena Kumari, David M. Nathan, Reedik Mägi, Solomon K. Musani, U de Faire, Knut Borch-Johnsen, Masahiro Koseki, Giuseppe Paolisso, Norman Klopp, Caroline S. Fox, Nelson B. Freimer, Mika Kähönen, Peter Henneman, Diana Zelenika, K Willems-Vandijk, Steven A. McCarroll, Paul Elliott, Wichmann H-E., J. C. Bis, Nita G. Forouhi, Antti Jula, Witteman Jcm., Fredrik Karpe, Joseph Hung, Antje Fischer-Rosinsky, Eric J. Brunner, Elena Gonzalez, Soumya Raychaudhuri, Jian'an Luan, Josée Dupuis, Joshua C. Randall, Taesung Park, Francis S. Collins, Lori L. Bonnycastle, Andrew A. Hicks, Peter Kovacs, Thomas Illig, Maja Barbalić, David Couper, Jaspal S. Kooner, Damien C. Croteau-Chonka, Gavin Lucas, P J Wagner, Young-Jin Kim, Yurii S. Aulchenko, Aurelian Bidulescu, Ingrid Meulenbelt, Pilar Galan, Iris M. Heid, Michael N. Weedon, Serena Sanna, Sarah H. Wild, Hivert M-F., Patricia B. Munroe, Johan G. Eriksson, Teresa Ferreira, Robert A. Scott, A. Sandbaek, Kenneth Rice, Veronique Vitart, Xin Yuan, Leslie A. Lange, Hilma Holm, Jorge R. Kizer, Timothy M. Frayling, Marika Kaakinen, Liu C-T., Petersen A-K., Peter Schwarz, G B Walters, Palmer Cna., Jean Tichet, Bernhard Paulweber, Ying Wu, Alyson Hall, Christopher T. Johansen, David Masson, Martin Ladouceur, Christie M. Ballantyne, Tai E-S., Robert Luben, Guillaume Charpentier, Angela Döring, Philip J. Barter, Ruth McPherson, Benjamin F. Voight, Wolfgang Rathmann, Mark Walker, Markus Perola, M. A. Province, Veikko Salomaa, James B. Meigs, George Davey Smith, Robert Clarke, Gerard Waeber, Stefania Bandinelli, Sally L. Ricketts, Kaisa Silander, Loos Rjf., Amanda J. Bennett, John C. Chambers, Marilyn C. Cornelis, L A Cupples, Andrew T. Hattersley, M Sandhu, Marju Orho-Melander, C M van Duijn, Olli T. Raitakari, David Meyre, Ida Surakka, Jouke-Jan Hottenga, Uh H-W., Kari Stefansson, David Melzer, P E Slagboom, Kristian Midthjell, Robert K. Semple, James P. Pirruccello, Aloysius G Lieverse, Åsa Johansson, Michael Roden, Felicity Payne, Eric J.G. Sijbrands, N P Burtt, David R. Hillman, Michael Marmot, Todd Green, Eric E. Schadt, Sijbrands Ejg., Tien Yin Wong, Coin Ljm., K B Boström, Olov Rolandsson, A D Morris, David Altshuler, Harald Grallert, L C Groop, Alan F. Wright, Karen Kapur, Xueling Sim, Philippe Froguel, K O Kyvik, T. Lauritzen, Linda S. Adair, Yavuz Ariyurek, Talin Haritunians, Toshiko Tanaka, Albert Hofman, MariaGrazia Franzosi, Nicholas L. Smith, Laura Crisponi, Andrew B. Singleton, A Uitterlinden, Bo Isomaa, Y A Kesaniemi, Anne U. Jackson, Christa Meisinger, Holly E. Syddall, Dorret I. Boomsma, Harry Campbell, Gonçalo R. Abecasis, Lyudmyla Kedenko, Christine Cavalcanti-Proença, G Crawford, Scott M. Grundy, Johnson Prv., Nuotio M-L., I Chen, J.H. Smit, Anuj Goel, M Li, David P. Strachan, Kenechi Ejebe, Beverley Balkau, Neelam Hassanali, Kristian Hveem, Pierre Meneton, R. Gwilliam, A J Swift, Caroline Hayward, J. Graessler, Carina Zabena, B. St Pourcain, Michel Marre, Margot Haun, Lyytikäinen L-P., Ben A. Oostra, Stefan Coassin, M. van Hoek, Nigel W. Rayner, John R. Thompson, Kurt Lohman, Ulla Sovio, Unnur Thorsteinsdottir, Naveed Sattar, Lyle J. Palmer, Ulf Gyllensten, A Elliott, Muredach P. Reilly, A Swift, Luigi Ferrucci, Syvänen A-C., Simon C. Potter, T.W. van Haeften, G Wu, Stefan Böhringer, Grant W. Montgomery, Edward G. Lakatta, Serkalem Demissie, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Hugh Watkins, Johanna Kuusisto, Lars Lind, Stefan R. Bornstein, Laura J. Rasmussen-Torvik, Terho Lehtimäki, Guillaume Paré, Sophie Visvikis-Siest, S C Heath, David Schlessinger, Juha Sinisalo, Kao Whl., Mark E. Cooper, Kati Kristiansson, Thomas W. Winkler, Thomas Sparsø, Laura J. McCulloch, Taina K. Lajunen, Alex N. Parker, Nabila Bouatia-Naji, Markku S. Nieminen, Peter Vollenweider, Wendy L. McArdle, G K Hovingh, Thomas A. Buchanan, Avan Aihie Sayer, M C Zillikens, Jing Hua Zhao, Naomi Hammond, Vilmundur Gudnason, Björn Zethelius, Panos Deloukas, Jacqueline C. M. Witteman, Eric Boerwinkle, Manuel Serrano-Ríos, Anna L. Gloyn, Katherine S. Elliott, A C Fedson, Torben Jørgensen, Nicole Soranzo, Heather M. Stringham, Bruce M. Psaty, A G Uitterlinden, Stavroula Kanoni, Christian Hengstenberg, Yun Li, Olle Melander, Alan R. Tall, Manuela Uda, Magnusson Pke., Christopher W. Kuzawa, V Mooser, R. M. van Dam, Jerome I. Rotter, Greenwood Cmt., Cyrus Cooper, Pau Navarro, Min Jin Go, Nancy L. Pedersen, Serge Hercberg, Bernhard O. Boehm, Eleanor Wheeler, Epidemiology, Medical Microbiology & Infectious Diseases, Clinical Genetics, Dastani, Z, Hivert, Mf, Timpson, N, Perry, Jr, Yuan, X, Scott, Ra, Henneman, P, Heid, Im, Kizer, Jr, Lyytikäinen, Lp, Fuchsberger, C, Tanaka, T, Morris, Ap, Small, K, Isaacs, A, Beekman, M, Coassin, S, Lohman, K, Qi, L, Kanoni, S, Pankow, J, Uh, Hw, Wu, Y, Bidulescu, A, Rasmussen Torvik, Lj, Greenwood, Cm, Ladouceur, M, Grimsby, J, Manning, Ak, Liu, Ct, Kooner, J, Mooser, Ve, Vollenweider, P, Kapur, Ka, Chambers, J, Wareham, Nj, Langenberg, C, Frants, R, Willems Vandijk, K, Oostra, Ba, Willems, Sm, Lamina, C, Winkler, Tw, Psaty, Bm, Tracy, Rp, Brody, J, Chen, I, Viikari, J, Kähönen, M, Pramstaller, Pp, Evans, Dm, St Pourcain, B, Sattar, N, Wood, Ar, Bandinelli, S, Carlson, Od, Egan, Jm, Böhringer, S, van Heemst, D, Kedenko, L, Kristiansson, K, Nuotio, Ml, Loo, Bm, Harris, T, Garcia, M, Kanaya, A, Haun, M, Klopp, N, Wichmann, He, Deloukas, P, Katsareli, E, Couper, Dj, Duncan, Bb, Kloppenburg, M, Adair, L, Borja, Jb, DIAGRAM+, Consortium, Magic, Consortium, Glgc, Investigator, Muther, Consortium, Wilson, Jg, Musani, S, Guo, X, Johnson, T, Semple, R, Teslovich, Tm, Allison, Ma, Redline, S, Buxbaum, Sg, Mohlke, Kl, Meulenbelt, I, Ballantyne, Cm, Dedoussis, Gv, Hu, Fb, Liu, Y, Paulweber, B, Spector, Td, Slagboom, Pe, Ferrucci, L, Jula, A, Perola, M, Raitakari, O, Florez, Jc, Salomaa, V, Eriksson, Jg, Frayling, Tm, Hicks, Aa, Lehtimäki, T, Smith, Gd, Siscovick, D, Kronenberg, F, van Duijn, C, Loos, Rj, Waterworth, Dm, Meigs, Jb, Dupuis, J, Richards, Jb, Voight, Bf, Scott, Lj, Steinthorsdottir, V, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Y, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Hofmann, Om, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Boström, Kb, Bravenboer, B, Bumpstead, S, Burtt, Np, Charpentier, G, Chines, P, Cornelis, M, Crawford, G, Doney, A, Elliott, K, Elliott, Al, Erdos, Mr, Fox, C, Franklin, C, Ganser, M, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Isomaa, B, Jackson, Au, Johnson, Pr, Jørgensen, T, Kao, Wh, Kong, A, Kraft, P, Kuusisto, J, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Lyssenko, V, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Narisu, N, Nilsson, P, Owen, Kr, Payne, F, Petersen, Ak, Platou, C, Proença, C, Prokopenko, I, Rathmann, W, Rayner, Nw, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Swift, Aj, Thorand, B, Tichet, J, Tuomi, T, van Dam, Rm, van Haeften, Tw, van Herpt, T, van Vliet Ostaptchouk, Jv, Walters, Gb, Weedon, Mn, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Collins, F, Gloyn, Al, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Laakso, M, Morris, Ad, Palmer, Cn, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Walker, M, Watanabe, Rm, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Pedersen, O, Barroso, I, Groop, L, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Froguel, P, van Duijn, Cm, Stefansson, K, Altshuler, D, Boehnke, M, Mccarthy, Mi, Soranzo, N, Wheeler, E, Glazer, Nl, Bouatia Naji, N, Mägi, R, Randall, J, Elliott, P, Rybin, D, Dehghan, A, Hottenga, Jj, Song, K, Goel, A, Lajunen, T, Cavalcanti Proença, C, Kumari, M, Timpson, Nj, Zabena, C, Ingelsson, E, An, P, O'Connell, J, Luan, J, Elliott, A, Roccasecca, Rm, Pattou, F, Sethupathy, P, Ariyurek, Y, Barter, P, Beilby, Jp, Ben Shlomo, Y, Bergmann, S, Bochud, M, Bonnefond, A, Borch Johnsen, K, Böttcher, Y, Brunner, E, Bumpstead, Sj, Chen, Yd, Clarke, R, Coin, Lj, Cooper, Mn, Crisponi, L, Day, In, de Geus, Ej, Delplanque, J, Fedson, Ac, Fischer Rosinsky, A, Forouhi, Ng, Franzosi, Mg, Galan, P, Goodarzi, Mo, Graessler, J, Grundy, S, Gwilliam, R, Hallmans, G, Hammond, N, Han, X, Hartikainen, Al, Hayward, C, Heath, Sc, Hercberg, S, Hillman, Dr, Hingorani, Ad, Hui, J, Hung, J, Kaakinen, M, Kaprio, J, Kesaniemi, Ya, Kivimaki, M, Knight, B, Koskinen, S, Kovacs, P, Kyvik, Ko, Lathrop, Gm, Lawlor, Da, Le Bacquer, O, Lecoeur, C, Li, Y, Mahley, R, Mangino, M, Martínez Larrad, Mt, Mcateer, Jb, Mcpherson, R, Meisinger, C, Melzer, D, Meyre, D, Mitchell, Bd, Mukherjee, S, Naitza, S, Neville, Mj, Orrù, M, Pakyz, R, Paolisso, Giuseppe, Pattaro, C, Pearson, D, Peden, Jf, Pedersen, Nl, Pfeiffer, Af, Pichler, I, Polasek, O, Posthuma, D, Potter, Sc, Pouta, A, Province, Ma, Rice, K, Ripatti, S, Rivadeneira, F, Rolandsson, O, Sandbaek, A, Sandhu, M, Sanna, S, Sayer, Aa, Scheet, P, Seedorf, U, Sharp, Sj, Shields, B, Sigurðsson, G, Sijbrands, Ej, Silveira, A, Simpson, L, Singleton, A, Smith, Nl, Sovio, U, Swift, A, Syddall, H, Syvänen, Ac, Tönjes, A, Uitterlinden, Ag, van Dijk, Kw, Varma, D, Visvikis Siest, S, Vitart, V, Vogelzangs, N, Waeber, G, Wagner, Pj, Walley, A, Ward, Kl, Watkins, H, Wild, Sh, Willemsen, G, Witteman, Jc, Yarnell, Jw, Zelenika, D, Zethelius, B, Zhai, G, Zhao, Jh, Zillikens, Mc, Diagram, Consortium, Giant, Consortium, Global B., Pgen Consortium, Borecki, Ib, Meneton, P, Magnusson, Pk, Nathan, Dm, Williams, Gh, Silander, K, Bornstein, Sr, Schwarz, P, Spranger, J, Karpe, F, Shuldiner, Ar, Cooper, C, Serrano Ríos, M, Lind, L, Palmer, Lj, Hu FB, 1st, Franks, Pw, Ebrahim, S, Marmot, M, Wright, Af, Stumvoll, M, Hamsten, A, Procardis, Consortium, Buchanan, Ta, Valle, Tt, Rotter, Ji, Penninx, Bw, Boomsma, Di, Cao, A, Scuteri, A, Schlessinger, D, Uda, M, Ruokonen, A, Jarvelin, Mr, Peltonen, L, Mooser, V, Magic, Investigator, Glgc, Consortium, Musunuru, K, Smith, Av, Edmondson, Ac, Stylianou, Im, Koseki, M, Pirruccello, Jp, Chasman, Di, Johansen, Ct, Fouchier, Sw, Peloso, Gm, Barbalic, M, Ricketts, Sl, Bis, Jc, Feitosa, Mf, Orho Melander, M, Melander, O, Li, X, Cho, Y, Go, Mj, Kim, Yj, Lee, Jy, Park, T, Kim, K, Sim, X, Ong, Rt, Croteau Chonka, Dc, Lange, La, Smith, Jd, Ziegler, A, Zhang, W, Zee, Ry, Whitfield, Jb, Thompson, Jr, Surakka, I, Smit, Jh, Sinisalo, J, Scott, J, Saharinen, J, Sabatti, C, Rose, Lm, Roberts, R, Rieder, M, Parker, An, Pare, G, O'Donnell, Cj, Nieminen, M, Nickerson, Da, Montgomery, Gw, Mcardle, W, Masson, D, Martin, Ng, Marroni, F, Lucas, G, Luben, R, Lokki, Ml, Lettre, G, Launer, Lj, Lakatta, Eg, Laaksonen, R, König, Ir, Khaw, Kt, Kaplan, Lm, Johansson, Å, Janssens, Ac, Igl, W, Hovingh, Gk, Hengstenberg, C, Havulinna, A, Hastie, Nd, Harris, Tb, Haritunians, T, Hall, A, Groop, Lc, Gonzalez, E, Freimer, Nb, Erdmann, J, Ejebe, Kg, Döring, A, Dominiczak, Af, Demissie, S, de Faire, U, Caulfield, Mj, Boekholdt, Sm, Assimes, Tl, Quertermous, T, Seielstad, M, Wong, Ty, Tai, E, Feranil, Ab, Kuzawa, Cw, Taylor HA, Jr, Gabriel, Sb, Holm, H, Gudnason, V, Krauss, Rm, Ordovas, Jm, Munroe, Pb, Tall, Ar, Hegele, Ra, Kastelein, Jj, Schadt, Ee, Strachan, Dp, Reilly, Mp, Samani, Nj, Schunkert, H, Cupples, La, Ridker, Pm, Rader, Dj, Kathiresan, S., Medical Research Council (MRC), Perry, John [0000-0001-6483-3771], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Semple, Robert [0000-0001-6539-3069], Griffin, Simon [0000-0002-2157-4797], Barroso, Ines [0000-0001-5800-4520], Soranzo, Nicole [0000-0003-1095-3852], Wheeler, Eleanor [0000-0002-8616-6444], Luan, Jian'an [0000-0003-3137-6337], Forouhi, Nita [0000-0002-5041-248X], Sharp, Stephen [0000-0003-2375-1440], Sovio, Ulla [0000-0002-0799-1105], Zhao, Jing Hua [0000-0003-4930-3582], Luben, Robert [0000-0002-5088-6343], Khaw, Kay-Tee [0000-0002-8802-2903], Sandhu, Manjinder [0000-0002-2725-142X], Apollo - University of Cambridge Repository, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Lifestyle, Overweight and Diabetes, Other departments, Experimental Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Cardiology, Human genetics, Psychiatry, NCA - Attention & Cognition, EMGO - Lifestyle, overweight and diabetes, Lääketieteen yksikkö - School of Medicine, University of Tampere, Institute for Molecular Medicine Finland, Hjelt Institute (-2014), Clinicum, Department of General Practice and Primary Health Care, Department of Public Health, Haartman Institute (-2014), Transplantation Laboratory, Biostatistics Helsinki, Quantitative Genetics, Complex Disease Genetics, Genetic Epidemiology, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., and O'Leary, DH.
Subjects: Netherlands Twin Register (NTR), Male, Insulin Resistance/genetics, VARIANTS, 0302 clinical medicine, POPULATION, African Americans, blood/genetics, 0303 health sciences, education.field_of_study, Adiponectin/blood, Adiponectin/genetics, Asian Continental Ancestry Group, Cholesterol, HDL/genetics, Diabetes Mellitus, Type 2/genetics, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Global B Pgen Consortium, MAGIC investigators, 3. Good health, Cholesterol, Medicine, Adiponectin, Type 2, medicine.medical_specialty, HDL, Biolääketieteet - Biomedicine, Single-nucleotide polymorphism, DIAGRAM Consortium, White People, Molecular Genetics, GLGC Consortium, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, GIANT Consortium, Diabetes Mellitus, Genetics, DIAGRAM+ Consortium, GENOME-WIDE ASSOCIATION, Polymorphism, education, Biology, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 0604 Genetics, Science & Technology, GLGC Investigators, nutritional and metabolic diseases, ta3121, medicine.disease, Obesity, Black or African American, blood/genetics, African Americans, Asian Continental Ancestry Group, Cholesterol, genetics, Diabetes Mellitus, genetics, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Insulin Resistance, genetics, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Endocrinology, Diabetes Mellitus, Type 2, Developmental Biology, Type 2/genetics, Cancer Research, Type 2 diabetes, QH426-470, 030204 cardiovascular system & hematology, LIPID CONCENTRATIONS, GENETICS & HEREDITY, Genetics (clinical), RISK, 2. Zero hunger, INSULIN-RESISTANCE, Glucose tolerance test, medicine.diagnostic_test, MAGIC Consortium, Single Nucleotide, ADIPOSE-TISSUE, CORONARY-ARTERY-DISEASE, Life Sciences & Biomedicine, Research Article, Clinical Research Design, GENETIC-BASIS, Population, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, ddc:610, 030304 developmental biology, RECEPTOR, Cholesterol, HDL, Human Genetics, HDL/genetics, 3121 General medicine, internal medicine and other clinical medicine, MuTHER Consortium, 3111 Biomedicine, Procardis Consortium, Insulin Resistance
Abstract: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p, Author Summary Serum adiponectin levels are highly heritable and are inversely correlated with the risk of type 2 diabetes (T2D), coronary artery disease, stroke, and several metabolic traits. To identify common genetic variants associated with adiponectin levels and risk of T2D and metabolic traits, we conducted a meta-analysis of genome-wide association studies of 45,891 multi-ethnic individuals. In addition to confirming that variants at the ADIPOQ and CDH13 loci influence adiponectin levels, our analyses revealed that 10 new loci also affecting circulating adiponectin levels. We demonstrated that expression levels of several genes in these candidate regions are associated with serum adiponectin levels. Using a powerful novel method to assess the contribution of the identified variants with other traits using summary-level results from large-scale GWAS consortia, we provide evidence that the risk alleles for adiponectin are associated with deleterious changes in T2D risk and metabolic syndrome traits (triglycerides, HDL, post-prandial glucose, insulin, and waist-to-hip ratio), demonstrating that the identified loci, taken together, impact upon metabolic disease.
Published: 2012

104. A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol

Author: Nancy L. Pedersen, Antti J. Kangas, James F. Wilson, Anke Toenjes, Ben A. Oostra, Janina S. Ried, Theodore Papamarkou, Angela Doering, Zoltán Kutalik, André G. Uitterlinden, Nicholas G. Martin, Antti Jula, Tõnu Esko, Bruce H. R. Wolffenbuttel, Lennart C. Karssen, Pirkka-Pekka Laurila, Åsa Johansson, Gerjan Navis, Aarno Palotie, Christian Gieger, Cisca Wijmenga, Peter P. Pramstaller, Aaron Isaacs, Inga Prokopenko, Jouke-Jan Hottenga, Massimo Mangino, Antti-Pekka Sarin, Ida Surakka, Veikko Salomaa, Taina Rantanen, Ulf Gyllensten, Nicole Soranzo, Jacqueline C.M. Witteman, Cornelia M. van Duijn, Samuli Ripatti, Albert Hofman, Nicholas W.J. Wainwright, Pasi Soininen, Leena Peltonen, Rita P. S. Middelberg, Pim van der Harst, Kirsten Ohm Kyvik, Dorret I. Boomsma, Harry Campbell, John Whitfield, Ann-Kristin Petersen, Vasiliki Lagou, Tim D. Spector, Wilmar Igl, Markus Perola, Florian Kronenberg, Maksim Struchalin, Nelson B. Freimer, Mika Kähönen, Jaakko Kaprio, Irene Mateo Leach, Fernando Rivadeneira, Mark I. McCarthy, Mika Ala-Korpela, Jorma Viikari, Andres Metspalu, Johan G. Eriksson, Eco J. C. de Geus, H.-Erich Wichmann, Grant W. Montgomery, M. S. Sandhu, Olli T. Raitakari, Michael Stumvoll, Terho Lehtimäki, Marja-Riitta Taskinen, Gonneke Willemsen, Andrew C. Heath, Igor Rudan, Yurii S. Aulchenko, Marjo-Riitta Jaervelin, Emmi Tikkanen, Claudia Lamina, Dawn M. Waterworth, Taskinen M.R., ENGAGE Consortium, Gibson, Greg, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Center for Liver, Digestive and Metabolic Diseases (CLDM), Biological Psychology, EMGO+ - Mental Health, Epidemiology, Internal Medicine, Clinical Genetics, Institute for Molecular Medicine Finland, Department of Medical and Clinical Genetics, Department of Medicine, Hjelt Institute (-2014), Department of Public Health, Department of General Practice and Primary Health Care, Biostatistics Helsinki, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genetic Epidemiology, and Medical Research Council (MRC)
Subjects: Netherlands Twin Register (NTR), Adipose Tissue/metabolism, Body Fat Distribution, Cadherins/genetics, Cholesterol/blood, Cholesterol/genetics, Chromosome Mapping, Chromosomes, Human, Pair 4/genetics, European Continental Ancestry Group/genetics, Genome-Wide Association Study, Genotype, Humans, Lipids/blood, Lipids/genetics, Lipoproteins/blood, Lipoproteins/genetics, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci/genetics, Risk Factors, Triglycerides/blood, Triglycerides/genetics, Waist-Hip Ratio, Genome-wide association study, 0302 clinical medicine, Genetics(clinical), Aetiology, 0303 health sciences, education.field_of_study, ta3141, ta3142, ASSOCIATION, Cadherins, Lipids, 3. Good health, Cholesterol, Adipose Tissue, DENSITY-LIPOPROTEIN CHOLESTEROL, TRIGLYCERIDE, Chromosomes, Human, Pair 4, SMOKING, Human, Lipoproteins, education, European Continental Ancestry Group, Quantitative Trait Loci, Locus (genetics), White People, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Clinical Research, Genome-Wide Association Studies, Genetics, Polymorphism, Biology, Molecular Biology, POLYMORPHISMS, Ecology, Evolution, Behavior and Systematics, 0604 Genetics, HDL CHOLESTEROL, Science & Technology, Density-lipoprotein cholesterol, HDL chloesterol, Association, Gene, Smoking, Plasma, Triglyeride, Obesity, Polymorphisms, Developmental Biology, Cancer Research, 030204 cardiovascular system & hematology, Waist–hip ratio, 2.1 Biological and endogenous factors, GENETICS & HEREDITY, Genetics (clinical), PLASMA, Single Nucleotide, ENGAGE Consortium, Pair 4/genetics, Pair 4, OBESITY, Life Sciences & Biomedicine, Research Article, LIPIDS, lcsh:QH426-470, Population, Quantitative trait locus, Chromosomes, gene, waist-to-hip ratio, cholesterol, Allele, Triglycerides, 030304 developmental biology, Whites, Human Genome, Human Genetics, Heritability, GENE, Protocadherins, lcsh:Genetics, 3111 Biomedicine
Abstract: Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene–environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10−9. There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus., Author Summary Circulating serum lipids contribute greatly to the global health by affecting the risk for cardiovascular diseases. Serum lipid levels are partly inherited, and already 95 loci affecting high- and low-density lipoprotein cholesterol, total cholesterol, and triglycerides have been found. Serum lipids are also known to be affected by multiple epidemiological risk factors like body composition, lifestyle, and sex. It has been hypothesized that there are loci modifying the effects between risk factors and serum lipids, but to date only candidate gene studies for interactions have been reported. We conducted a genome-wide screen with meta-analysis approach to identify loci having interactions with epidemiological risk factors on serum lipids with over 30,000 population-based samples. When combining results from our initial datasets and 8 additional replication cohorts (maximum N = 17,102), we found a genome-wide significant locus in chromosome 4p15 with a joint P-value of 4.79×10−9 modifying the effect of waist-to-hip ratio on total cholesterol. In the area surrounding this genetic variant, there were two genes having association between the genotypes and the gene expression in adipose tissue, and we also found enrichment of association in genes belonging to lipid metabolism related functions.
Published: 2011

105. Correction for Schumann et al., Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

Author: Paul F. O'Reilly, Eco J. C. de Geus, Massimo Mangino, Giuseppe Matullo, Anokhi Ali Khan, Joline W.J. Beulens, Stéphane Cauchi, Fazil Aliev, Nicholas J. Wareham, Eugenio Santos, Najaf Amin, Dale R. Nyholt, Ruth J. F. Loos, Peter Vollenweider, Diederick E. Grobbee, Norbert Dahmen, Anke Tönjes, Angela Doering, Nicole Vogelzangs, Michiel L. Bots, Jean-Antoine Girault, Georgy Bakalkin, Cuno S.P.M. Uiterwaal, Andres Metspalu, Pimphen Charoen, David Stacey, Toni-Kim Clarke, Ulrike Heberlein, Jaana Laitinen, John C. Chambers, Francesca Ducci, André G. Uitterlinden, James Scott, Rudolf A. de Boer, Vincent Mooser, Cornelia M. van Duijn, Lachlan J. M. Coin, Gérard Waeber, Christian Mueller, Marjo-Riitta Järvelin, Pim van der Harst, Kijoung Song, Jing Hua Zhao, Gunter Schumann, Daniel F. Gudbjartsson, Weihua Zhang, Dawn M. Waterworth, Michael Stumvoll, Claire Troakes, Sylvane Desrivières, Nelson B. Freimer, Tatiana Foroud, Brenda W.J.H. Penninx, Jaspal S. Kooner, Mark I. McCarthy, Mattijs E. Numans, Tonu Esk, Jian'an Luan, Yurii S. Aulchenko, Ida Surakk, Andrew Heath, Inga Prokopenko, Ben A. Oostra, Stephan J. L. Bakker, Nicholas G. Martin, Simonetta Guarrera, Fulvio Ricceri, Xin Yuan, Alberto Fernández-Medarde, John Whitfield, Alanna C. Easton, Paul Elliott, Thorarinn Tyrfingsson, Howard J. Edenberg, Stéphane Lobbens, Elemi J. Breetvelt, Johannes H. Smit, Gonneke Willemsen, Rainer Spanagel, Oliver Staehlin, Ainhoa Bilbao, Alejandro Núñez, Kay-Tee Khaw, Tim D. Spector, Guangju Zhai, Victor Hesselbrock, Jaakko Kaprio, Anna-Liisa Hartikainen, Beverley Balkau, Jouke-Jan Hottenga, Kari Stefansson, Anbarasu Lourdusamy, Albert Hofman, Danielle M. Dick, Charlotte Onland-Moret, Wolfgang H. Sommer, Christine Cavalcanti-Proença, Paolo Vineis, Anneli Pouta, Matti Isohanni, Leena Peltonen, Jacqueline C.M. Witteman, Silvia Polidoro, Thorgeir E. Thorgeirsson, Yvonne T. van der Schouw, Nicole Soranzo, Matthieu Maroteaux, Delphine Beury, Erich Wichmann, Gerjan Navis, Karen H. Berger, Brigitte Kuehnel, Ulla Sovio, Unnur Thorsteinsdottir, Miklós Palkovits, and Dorret I. Boomsma
Subjects: Gerontology, Genetics, Multidisciplinary, Political science, AUTISM SUSCEPTIBILITY CANDIDATE 2, Correction, Genome-wide association study, Functional studies, Gene, Alcohol consumption
Published: 2011

106. Carriage of the V279F Null Allele within the Gene Encoding Lp-PLA2 Is Protective from Coronary Artery Disease in South Korean Males

Author: Hyo Jeong Ku, Yangsoo Jang, Il Young Oh, Kyung Woo Park, Hyo-Soo Kim, Dawn M. Waterworth, Patrick Vallance, Bok Soo Lee, Kijoung Song, Jeong Euy Park, Bok Ghee Han, Dong Jik Shin, Hyun Jai Cho, Vincent Mooser, John C. Whittaker, Sun Ha Jee, Eunyoung Cho, Hye Yoon Jang, Lon R. Cardon, Sujin Kim, Jong Eun Lee, and Jong Ho Lee
Subjects: Genetics, medicine.medical_specialty, Multidisciplinary, business.industry, medicine.disease, Null allele, Gastroenterology, Coronary artery disease, Internal medicine, Diabetes mellitus, Genotype, medicine, Myocardial infarction, Allele, business, Body mass index, Allele frequency
Abstract: Background The Asia-specific PLA2G7 994G-T transversion leads to V279F substitution within the lipoprotein-associated phospholipase-A2 (Lp-PLA2) and to absence of enzyme activity in plasma. This variant offers a unique natural experiment to assess the role of Lp-PLA2 in the pathogenesis of coronary artery disease (CAD) in humans. Given conflicting results from mostly small studies, a large two-stage case-control study was warranted. Methodology/Principal Findings PLA2G7 V279F genotypes were initially compared in 2890 male cases diagnosed with CAD before age 60 with 3128 male controls without CAD at age 50 and above and subsequently in a second independent male dataset of 877 CAD cases and 1230 controls. In the first dataset, the prevalence of the 279F null allele was 11.5% in cases and 12.8% in controls. After adjustment for age, body mass index, diabetes, smoking, glucose and lipid levels, the OR (95% CI) for CAD for this allele was 0.80 (0.66–0.97, p = 0.02). The results were very similar in the second dataset, despite lower power, with an allele frequency of 11.2% in cases and 12.5% in controls, leading to a combined OR of 0.80 (0.69–0.92), p = 0.002. The magnitude and direction of this genetic effect were fully consistent with large epidemiological studies on plasma Lp-PLA2 activity and CAD risk. Conclusions Natural deficiency in Lp-PLA2 activity due to carriage of PLA2G7 279F allele protects from CAD in Korean men. These results provide evidence for a causal relationship between Lp-PLA2 and CAD, and support pharmacological inhibition of this enzyme as an innovative way to prevent CAD.
Published: 2011

107. Erratum: Corrigendum: Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

Author: Vincent Mooser, Claire E H M Donjacour, Frans H.J. Claas, Willem Verduijn, Sebastiaan Overeem, Peter Geisler, Geert Mayer, Gert J. Lammers, José L. Vicario, Julie Vienne Bürki, Joan Santamaria, Michel Billiard, Peter Vollenwider, Sven Bergmann, Michel Lecendreux, Claudio L. Bassetti, Isabelle Arnulf, Antonio Benetó, Raphael Heinzer, Stine Knudsen, Corinne Pfister, Guadalupe Ercilla, Jacques S. Beckmann, Rosa Peraita Adrados, Zoltán Kutalik, Johannes Mathis, Gérard Didelot, Armand Valsesia, Hyun Hor, Alex Iranzo, Gérard Waeber, Mehdi Tafti, Yves Dauvilliers, Dawn M. Waterworth, Ioannis Theodorou, Poul Jennum, and Brice Petit
Subjects: Hla class ii, Genetics, Haplotype, medicine, Genome-wide association study, Biology, medicine.disease, Narcolepsy
Abstract: Corrigendum: Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy
Published: 2011

108. Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease

Author: Philip J. Barter, Ruth McPherson, Sally L. Ricketts, David Hadley, Manjinder S. Sandhu, Nilesh J. Samani, Aimo Ruokonen, Panagiotis Deloukas, Eleanor Wheeler, Anne U. Jackson, Lon R. Cardon, Jing Hua Zhao, Robert Luben, Ida Surakka, Veikko Salomaa, Noha Lim, Karen L. Mohlke, Li Chen, Peter Vollenweider, Jian'an Luan, Jacqueline C. M. Witteman, Robert E. L. Roberts, Weihua Zhang, Yurii S. Aulchenko, Paul Elliott, Scott M Grundy, Y. Antero Kesäniemi, Serena Sanna, John R. Thompson, Sheila A. Rodwell, Daniel J. Rader, Elizabeth H. Young, Alistair S. Hall, Peter S. Braund, Hakon Hakonarson, Gérard Waeber, Jaspal S. Kooner, Robert W. Mahley, Toby Johnson, Stephen E. Epstein, Nicholas J. Wareham, Cornelia M. van Duijn, Samuli Ripatti, Kay-Tee Khaw, Michael Boehnke, John C. Chambers, Muredach P. Reilly, Vincent Mooser, Michael Inouye, Kijoung Song, Sofie Ashford, J. Tuomilehto, Dawn M. Waterworth, David P. Strachan, Inês Barroso, Leena Peltonen, Xin Yuan, Alexandre F.R. Stewart, Marjo-Riitta Järvelin, David Schlessinger, Angelo Scuteri, Maksim Struchalin, Ruth J. F. Loos, Gonçalo R. Abecasis, S. Matthijs Boekholdt, Wendy L. McArdle, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Epidemiology, and Wellcome Trust Case Control Consortium
Subjects: Single-nucleotide polymorphism, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Biology, Asian Continental Ancestry Group, Cholesterol, HDL/blood, Cholesterol, HDL/genetics, Cholesterol, LDL/blood, Cholesterol, LDL/genetics, Coronary Artery Disease/genetics, European Continental Ancestry Group, Genetic Variation, Genome-Wide Association Study, Humans, Lipid Metabolism/genetics, Polymorphism, Single Nucleotide, Risk Factors, Triglycerides/blood, Triglycerides/genetics, Colaus Study, Bioinformatics, Article, White People, Coronary artery disease, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Asian People, Genetic variation, medicine, Risk factor, Allele, Triglycerides, 030304 developmental biology, Genetics, 0303 health sciences, Cholesterol, Cholesterol, HDL, Lipid metabolism, Cholesterol, LDL, medicine.disease, Lipid Metabolism, chemistry, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine
Abstract: Objective— Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Methods and Results— We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10 −8 to 3.1×10 −10 ). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2 , APOB , APOE-C1-C4-C2 cluster, LPL , ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10 −3 to 1.2×10 −9 ). Conclusion— We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.
Published: 2010

109. Meta-Analysis of 28,141 Individuals Identifies Common Variants within Five New Loci That Influence Uric Acid Concentrations

Author: Angela Doering, Jacques S. Beckmann, Patricia B. Munroe, Alan F. Wright, Peter Vollenweider, Peter P. Pramstaller, M. Perola, Veikko Salomaa, Murielle Bochud, James F. Wilson, Sven Bergmann, Henry Völzke, Georg Homuth, Igor Rudan, Thomas Meitinger, Christian Gieger, Leena Peltonen, Martin Farrall, Jerzy Adamski, Anna F. Dominiczak, Mark J. Caulfield, H.-Erich Wichmann, Gérard Waeber, John Whitfield, Tim D. Spector, Uwe Völker, John M. C. Connell, Holger Prokisch, Åsa Johansson, Yurii S. Aulchenko, Harry Campbell, Veronique Vitart, Morris J. Brown, Rui Wang-Sattler, David Schlessinger, Mark I. McCarthy, Nilesh J. Samani, Massimo Mangino, Manuela Uda, John F. Peden, Serena Sanna, Chris Wallace, Perttu Salo, Ramaiah Nagaraja, Alexander Teumer, Ulf Gyllensten, Eva Albrecht, Dale R. Nyholt, Hugh Watkins, Matthias Nauck, Thomas Illig, Claudia Lamina, Dawn M. Waterworth, Melanie Kolz, Vincent Mooser, and Toby Johnson
Subjects: Male, genome-wide association, urate-anion exchanger, triglyceride levels, fasting glucose, serum urate, carnitine, gout, transport, protein, risk, Cancer Research, Gout, Urate transport, chemistry.chemical_compound, 0302 clinical medicine, Hyperuricemia, Genetics and Genomics/Genetics of Disease, Genetics (clinical), Genetics and Genomics/Medical Genetics, Genetics, 0303 health sciences, Computational Biology/Systems Biology, biology, Genetics and Genomics/Functional Genomics, 3. Good health, Female, Genetic Variation, Genome-Wide Association Study, Gout/etiology, Humans, Uric Acid/blood, Colaus Study, Genetics and Genomics/Gene Discovery, SLC22A12, Research Article, medicine.medical_specialty, lcsh:QH426-470, Public Health and Epidemiology, Single-nucleotide polymorphism, Genetics and Genomics/Complex Traits, Computational Biology/Molecular Genetics, 03 medical and health sciences, Internal medicine, Genetics and Genomics/Population Genetics, medicine, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 030203 arthritis & rheumatology, uric acid, genome-wide association study, quantitative traits, genetics, Genetics and Genomics, medicine.disease, Uric Acid, Minor allele frequency, lcsh:Genetics, Endocrinology, chemistry, biology.protein, Uric acid, Public Health and Epidemiology/Epidemiology, Computational Biology/Population Genetics, SLC2A9
Abstract: Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2×10−201), ABCG2 (p = 3.1×10−26), SLC17A1 (p = 3.0×10−14), SLC22A11 (p = 6.7×10−14), SLC22A12 (p = 2.0×10−9), SLC16A9 (p = 1.1×10−8), GCKR (p = 1.4×10−9), LRRC16A (p = 8.5×10−9), and near PDZK1 (p = 2.7×10−9). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0×10−26) and propionyl-L-carnitine (p = 5.0×10−8) concentrations, which in turn were associated with serum UA levels (p = 1.4×10−57 and p = 8.1×10−54, respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels., Author Summary Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. The regulation of serum uric acid levels is under a strong genetic control. This study describes the first meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent. We show that common DNA variants at nine different loci are associated with uric acid concentrations, five of which are novel. These variants are located within the genes coding for organic anion transporter 4 (SLC22A11), monocarboxylic acid transporter 9 (SLC16A9), glucokinase regulatory protein (GCKR), Carmil (LRRC16A), and near PDZ domain-containing 1 (PDZK1). Gender-specific effects are shown for variants within the recently identified genes coding for glucose transporter 9 (SLC2A9) and the ATP-binding cassette transporter (ABCG2). Based on screening of 163 metabolites, we show an association of one of the identified variants within SLC16A9 with DL-carnitine and propionyl-L-carnitine. Moreover, DL-carnitine and propionyl-L-carnitine were strongly correlated with serum UA levels, forming a triangle between SNP, metabolites and UA levels. Taken together, these associations highlight pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia.
Published: 2009
Full Text: View/download PDF

110. Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design?

Author: Ruth J. F. Loos, Stefan Schreiber, Claude Bouchard, Unnur Thorsteinsdottir, Barbara Kollerits, Karani Santhanakrishnan Vimaleswaran, Shantanu Sengupta, Bernhard Paulweber, Rossella Sorice, Robert A. Hegele, Margret R. Hoehe, Thuy Trang Nguyen, Lu Qi, Gudmar Thorleifsson, Tuomo Rankinen, Cecilia M. Lindgren, Philippe Froguel, James C. Engert, Andreas Luchner, Karen L. Mohlke, Dieter Rosskopf, Almut Nebel, Francesc Francés, Henry Völzke, Steve E. Humphries, Helen N. Lyon, Vincent Mooser, Nan M. Laird, Steven C. Hunt, Jitender Kumar, Florian Kronenberg, Salim Yusuf, Thomas Illig, M. R. Järvelin, Christoph Lange, Anke Hinney, Christian Dina, Sonia S. Anand, Jackie A. Cooper, Birgit Langer, Iris M. Heid, Nicholas J. Wareham, Vera Adamkova, Kristin G. Ardlie, Louis Pérusse, Johannes Hebebrand, Cornelia Huth, Dolores Corella, Anita Suk, Peter Bjerregaard, Heike Biebermann, Eva Fisher, Dawn M. Waterworth, Marika Kaakinen, Shengxu Li, Leslie A. Lange, David Meyre, Jaroslav A. Hubacek, H-Erich Wichmann, Marina Ciullo, Heiko Krude, Mark I. McCarthy, Joel N. Hirschhorn, Frank B. Hu, Heiner Boeing, and Medical Research Council (MRC)
Subjects: Male, Cancer Research, obesity, LIVER, Medizin, PROTEIN, Bioinformatics, 0302 clinical medicine, INSIG2, GENETICS & HEREDITY, POPULATION, Genetics (clinical), METABOLIC SYNDROME, 0303 health sciences, education.field_of_study, Intracellular Signaling Peptides and Proteins, UPSTREAM, Middle Aged, INSULIN, Research Design, Meta-analysis, Female, Life Sciences & Biomedicine, Medical Genetics, Research Article, EXPRESSION, Adult, Adolescent, lcsh:QH426-470, Population, Public Health and Epidemiology, COMMON GENETIC VARIANT, Biology, Childhood obesity, 03 medical and health sciences, Young Adult, Genetics, medicine, Biochemical Phenomena, Metabolism, and Nutrition, Humans, Obesity, education, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 0604 Genetics, Science & Technology, Polymorphism, Genetic, Membrane Proteins, Odds ratio, BODY-MASS, medicine.disease, POLYMORPHISM, lcsh:Genetics, Genetics, Population, Metabolic syndrome, Body mass index, 030217 neurology & neurosurgery, Developmental Biology, Demography, Genome-Wide Association Study
Abstract: The INSIG2 rs7566605 polymorphism was identified for obesity (BMI≥30 kg/m2) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status (‘healthy population’, HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I2 measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I2 measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI≥32.5, 35.0, 37.5, 40.0 kg/m2 versus BMI, Author Summary A polymorphism of the INSIG2 gene was identified as being associated with obesity in one of the first genome-wide association studies. However, this association has since then been highly debated upon inconsistent subsequent reports. We collected association information from 34 studies including a total of 74,000 participants. In a meta-analysis of the 27 studies including 66,000 Caucasian adults, we found no overall association of this polymorphism rs7566605 with obesity, comparing subjects with a body-mass-index (BMI)≥30 kg/m2 with normal BMI subjects (BMI
Published: 2009
Full Text: View/download PDF

111. Age-Related Effects of Genetic Variation on Lipid Levels: The Columbia University BioMarkers Study

Author: Thomas J. Starc, Carmen R. Isasi, Steven Shea, Dawn M. Waterworth, Richard E. Deckelbaum, Emma Hawe, Lars Berglund, Philippa J. Talmud, Steve E. Humphries, and Henry N. Ginsberg
Subjects: Adult, Male, Heterozygote, medicine.medical_specialty, Adolescent, Genotype, Coronary Disease, Disease, White People, Gene Frequency, Internal medicine, Genetic variation, Cholesterylester transfer protein, medicine, Humans, Allele, Apolipoproteins C, Child, Medical History Taking, Glycoproteins, Apolipoprotein C-III, Lipoprotein lipase, biology, business.industry, Age Factors, Hispanic or Latino, Lipase, medicine.disease, Lipids, Obesity, Cholesterol Ester Transfer Proteins, Lipoprotein Lipase, Cholesterol, Phenotype, Endocrinology, Liver, Pediatrics, Perinatology and Child Health, biology.protein, Female, Hepatic lipase, Carrier Proteins, business, Biomarkers
Abstract: Objectives. To examine the genotype:phenotype association in children compared with their parents. Methods. Variations at 4 key gene loci, namely lipoprotein lipase (LPL S447X), hepatic lipase (HL −480C>T), cholesteryl ester transfer protein (CETP TaqIB), and apolipoprotein CIII (APOC3 −455T>C and −482C>T), were examined in children (n = 495) and their parents (n = 353) in the Columbia University BioMarkers Study, 1994 to 1998. Results. The frequencies of the rare alleles of theHL −480C>T and APOC3 −455T>C and −482C>T (but not LPL S447X or CETPTaqIB) were significantly lower in non-Hispanic white participants compared with Hispanics. Overall, genotype effects seen in the adults were weaker in the children, although similar trends were seen. In an examination of the effect of body fat on the genotypic effects in the children, there was significant HL−480C>T:sum of skinfold interaction. Conclusions. All genotypes were associated with clear relationships to plasma lipid levels in adults, but the effects were weaker in their children, unless stressed by body fat. atherosclerosis, cardiovascular disease, child, lipids, genetics.
Published: 2001

112. The contribution of genetic variation to the postprandial response: Results from the european atherosclerosis research study (Earsii)

Author: P.J. Talmud, Dawn M. Waterworth, and S.E. Humphries
Subjects: Genetics, Postprandial, Genetic variation, Biology, Cardiology and Cardiovascular Medicine
Published: 1999

113. 1.P.278 Genetic variation in the apolipoprotein CIII gene and effects on plasma triglyceride levels in a large prospective study

Author: George J. Miller, Dawn M. Waterworth, Philippa J. Talmud, and Steve E. Humphries
Subjects: medicine.medical_specialty, Endocrinology, Plasma triglyceride, Internal medicine, Genetic variation, medicine, Apolipoprotein CIII, Biology, Cardiology and Cardiovascular Medicine, Bioinformatics, Prospective cohort study, Gene
Published: 1997

114. 5' polymorphism of the CYP17 gene is not associated with serum testosterone levels in women with polycystic ovaries

Author: Dawn M. Waterworth, Neda Gharani, Steve Franks, and R Williamson
Subjects: Serum testosterone, medicine.medical_specialty, Polymorphism, Genetic, Genotype, business.industry, Endocrinology, Diabetes and Metabolism, Biochemistry (medical), Clinical Biochemistry, Steroid 17-alpha-Hydroxylase, Biochemistry, Polycystic ovary, Endocrinology, Cytochrome P-450 Enzyme System, Internal medicine, Humans, Medicine, Female, Testosterone, business, Gene, Alleles, Polycystic Ovary Syndrome
Published: 1996

115. Genetics and molecular biology

Author: Dawn M. Waterworth and Philippa J. Talmud
Subjects: Genetics, Nutrition and Dietetics, Parasitology, Endocrinology, Diabetes and Metabolism, Transgene, Cell Biology, Apolipoproteins b, Biology, Cardiology and Cardiovascular Medicine, Molecular Biology, Apolipoproteins E
Published: 1991

116. The Benefits of Using Genetic Information to Design Prevention Trials

Author: Meena Kumari, Chun Fang Xu, Li Li, Nan Bing, Mika Kivimäki, Cathie Spino, Youna Hu, Gonçalo R. Abecasis, Philippa J. Talmud, John C. Whittaker, Hyun Min Kang, Kijoung Song, Margaret G. Ehm, Aroon D. Hingorani, Matthew R. Nelson, and Dawn M. Waterworth
Subjects: Research design, medicine.medical_specialty, Genotype, Cost-Benefit Analysis, Myocardial Infarction, Genome-wide association study, Disease, Bioinformatics, Article, Statistical power, Macular Degeneration, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Genetics, medicine, Humans, Genetics(clinical), Genetic Testing, Intensive care medicine, Genetics (clinical), 030304 developmental biology, Genetic testing, Clinical Trials as Topic, 0303 health sciences, Models, Statistical, medicine.diagnostic_test, Cost–benefit analysis, business.industry, Genetic Variation, Genetic architecture, 3. Good health, Clinical trial, Diabetes Mellitus, Type 1, Phenotype, Diabetes Mellitus, Type 2, Research Design, business, 030217 neurology & neurosurgery
Abstract: Clinical trials for preventative therapies are complex and costly endeavors focused on individuals likely to develop disease in a short time frame, randomizing them to treatment groups, and following them over time. In such trials, statistical power is governed by the rate of disease events in each group and cost is determined by randomization, treatment, and follow-up. Strategies that increase the rate of disease events by enrolling individuals with high risk of disease can significantly reduce study size, duration, and cost. Comprehensive study of common, complex diseases has resulted in a growing list of robustly associated genetic markers. Here, we evaluate the utility--in terms of trial size, duration, and cost--of enriching prevention trial samples by combining clinical information with genetic risk scores to identify individuals at greater risk of disease. We also describe a framework for utilizing genetic risk scores in these trials and evaluating the associated cost and time savings. With type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), and advanced age-related macular degeneration (AMD) as examples, we illustrate the potential and limitations of using genetic data for prevention trial design. We illustrate settings where incorporating genetic information could reduce trial cost or duration considerably, as well as settings where potential savings are negligible. Results are strongly dependent on the genetic architecture of the disease, but we also show that these benefits should increase as the list of robustly associated markers for each disease grows and as large samples of genotyped individuals become available.
Full Text: View/download PDF

117. The epigenetic signature of systemic insulin resistance in obese women

Author: Anna-Stina Sahlqvist, Ingrid Dahlman, Anders Thorell, Xiang Yao, Johannes M. Freudenberg, Indranil Sinha, Toby Johnson, Deepak K. Rajpal, Peter Arner, Mikael Rydén, A. Katrina Loomis, Dawn M. Waterworth, Erik Näslund, and Huan Xu
Subjects: Adult, 0301 basic medicine, medicine.medical_specialty, Phosphofructokinase-2, Adipose Tissue, White, Endocrinology, Diabetes and Metabolism, Subcutaneous Fat, Adipose tissue, White adipose tissue, Type 2 diabetes, Intra-Abdominal Fat, Biology, Article, Epigenesis, Genetic, 03 medical and health sciences, Insulin resistance, Internal medicine, medicine, Internal Medicine, Humans, Obesity, Epigenetics, Adaptor Proteins, Signal Transducing, DNA methylation, Receptor-Like Protein Tyrosine Phosphatases, Class 3, food and beverages, Methylation, medicine.disease, 030104 developmental biology, Endocrinology, CpG site, Adipose Tissue, Diabetes Mellitus, Type 2, Visceral adipose tissue, Insulin Receptor Substrate Proteins, Leukocytes, Mononuclear, CpG island, Female, Erratum, Insulin Resistance, Collagen Type V, Biomarkers, Signal Transduction
Abstract: Aims/hypothesis Insulin resistance (IR) links obesity to type 2 diabetes. The aim of this study was to explore whether white adipose tissue (WAT) epigenetic dysregulation is associated with systemic IR by genome-wide CG dinucleotide (CpG) methylation and gene expression profiling in WAT from insulin-resistant and insulin-sensitive women. A secondary aim was to determine whether the DNA methylation signature in peripheral blood mononuclear cells (PBMCs) reflects WAT methylation and, if so, can be used as a marker for systemic IR. Methods From 220 obese women, we selected a total of 80 individuals from either of the extreme ends of the distribution curve of HOMA-IR, an indirect measure of systemic insulin sensitivity. Genome-wide transcriptome and DNA CpG methylation profiling by array was performed on subcutaneous (SAT) and visceral (omental) adipose tissue (VAT). CpG methylation in PBMCs was assayed in the same cohort. Results There were 647 differentially expressed genes (false discovery rate [FDR] 10%) in SAT, all of which displayed directionally consistent associations in VAT. This suggests that IR is associated with dysregulated expression of a common set of genes in SAT and VAT. The average degree of DNA methylation did not differ between the insulin-resistant and insulin-sensitive group in any of the analysed tissues/cells. There were 223 IR-associated genes in SAT containing a total of 336 nominally significant differentially methylated sites (DMS). The 223 IR-associated genes were over-represented in pathways related to integrin cell surface interactions and insulin signalling and included COL5A1, GAB1, IRS2, PFKFB3 and PTPRJ. In VAT there were a total of 51 differentially expressed genes (FDR 10%); 18 IR-associated genes contained a total of 29 DMS. Conclusions/interpretation In individuals discordant for insulin sensitivity, the average DNA CpG methylation in SAT and VAT is similar, although specific genes, particularly in SAT, display significantly altered expression and DMS in IR, possibly indicating that epigenetic regulation of these genes influences metabolism. Electronic supplementary material The online version of this article (doi:10.1007/s00125-016-4074-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Full Text: View/download PDF

118. Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies

Author: Thomas M. Morgan, Stephen P. Fortmann, Daniel B. Mirel, Christopher W. Knouff, Willem H. Ouwehand, Sekar Kathiresan, Dawn M. Waterworth, Ingo Ruczinski, Lewis C. Becker, Candace Guiducci, Alan S. Go, Brian G. Kral, Nicola Martinelli, Diane M. Becker, Ron Do, Michael Scholz, Gudmundur Thorgeirsson, Wibke Reinhard, J. Enrique Herrera, Themistocles L. Assimes, Mary Susan Burnett, Liming Qu, Pier Franco Pignatti, Hakon Hakonarson, Rosanna Asselta, Jean Yee, Stefano Duga, Rasika A. Mathias, M Walker, David M. Nathan, Gavin Lucas, Alexander F. Wilson, Roberto Elosua, Richard M. Myers, Martina Grassl, Leena Peltonen, Christa Meisinger, James C. Engert, Stephen E. Epstein, Wolfgang Lieb, Peter S. Braund, H.-Erich Wichmann, Benjamin J. Wright, Patrick Linsel-Nitschke, Mingyao Li, Stefan Schreiber, Klaus Berger, Gordon H. Williams, Alistair S. Hall, Karl Andersen, Jeanette Erdmann, Lisa R. Yanek, Andreas Ziegler, Nauder Faraday, Marcus Fischer, Stephen G. Ball, Yechiel Friedlander, Veikko Salomaa, Stephen M. Schwartz, Bhoom Suktitipat, Joseph M. Devaney, Klaus Stark, Panos Deloukas, Ron Waksman, Changchun Xie, Thomas Scheffold, Michael Preuss, Robert L. Wilensky, François Cambien, Devin Absher, Janina Winogradow, Yoonhee Kim, Andreas Huge, Unnur Thorsteinsdottir, Muredach P. Reilly, Christina Willenborg, Joan Sala, David S. Siscovick, Pascal P. McKeown, Joseph M. Lindsay, Gudmar Thorleifsson, Kenneth M. Kent, Daniel J. Rader, James B. Meigs, Benjamin F. Voight, John R. Thompson, Christopher B. Granger, Elisabetta Trabetti, Vincent Mooser, Stephen Sidney, Neil Risch, Domenico Girelli, Atif Qasim, John A. Spertus, Mark J. Daly, Shaun Purcell, Aki S. Havulinna, David Altshuler, Kari Stefansson, Dhananjay Vaidya, Carlos Iribarren, Christian Hengstenberg, Svati H. Shah, Rafael Ramos, Olle Melander, Mark A. Hlatky, Christopher Patterson, Anthony J. Balmforth, Giovanni Malerba, Calum A. MacRae, Melissa Parkin, William H. Matthai, Christopher J. O'Donnell, Jaume Marrugat, Kiran Musunuru, Monika Stoll, Anika Grosshennig, Augusto D. Pichard, Lowell F. Satler, Hua Tang, Joel N. Hirschhorn, Nilesh J. Samani, Inke R. König, Sandra Eifert, Joshua W. Knowles, Sonia S. Anand, Heribert Schunkert, Thomas Quertermous, Hilma Holm, Isaac Subirana, and Oliviero Olivieri
Subjects: Male, medicine.medical_specialty, Internationality, Kinesins, Single-nucleotide polymorphism, Genome-wide association study, 030204 cardiovascular system & hematology, Arginine, Polymorphism, Single Nucleotide, polymorphism, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Humans, Medicine, Prospective cohort study, 030304 developmental biology, Genetics, 0303 health sciences, kinesin-like protein 6, KIF6, business.industry, Hazard ratio, Tryptophan, Case-control study, Odds ratio, Middle Aged, medicine.disease, myocardial infarction, Case-Control Studies, coronary artery disease, Female, Cardiology and Cardiovascular Medicine, business, Genome-Wide Association Study
Abstract: Objectives We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). Background Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. Methods The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports. Results A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of >= 2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups. Conclusions The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study. (J Am Coll Cardiol 2010;56:1552-63) (C) 2010 by the American College of Cardiology Foundation
Full Text: View/download PDF

119. The Population Reference Sample, POPRES: A Resource for Population, Disease, and Pharmacological Genetics Research

Author: Peter Vollenweider, John C. Chambers, Linda P. Briley, Gérard Waeber, Matthew R. Nelson, Karen S. King, Eric H. Lai, Allen D. Roses, John Novembre, Stephen L. Hauser, Margaret G. Ehm, Jorge R. Oksenberg, Carlos Bustamante, Vincent Mooser, Adam R. Boyko, Dawn M. Waterworth, Yuka Maruyama, Heide A. Stirnadel, Jaspal S. Kooner, Katarzyna Bryc, Amit Indap, Brendan Jones, and Daniel K. Burns
Subjects: Male, Genotype, Population, Population genetics, Sample (statistics), Disease, Biology, Polymorphism, Single Nucleotide, Article, White People, Drug Hypersensitivity, 03 medical and health sciences, 0302 clinical medicine, Population Groups, Databases, Genetic, Genetics, Humans, Genetics(clinical), International HapMap Project, education, Genetics (clinical), Selection (genetic algorithm), 030304 developmental biology, 0303 health sciences, education.field_of_study, Genome, Human, Dideoxynucleosides, 3. Good health, Genetics, Population, Pharmacogenetics, Case-Control Studies, Human genome, Female, 030217 neurology & neurosurgery
Abstract: Technological and scientific advances, stemming in large part from the Human Genome and HapMap projects, have made large-scale, genome-wide investigations feasible and cost effective. These advances have the potential to dramatically impact drug discovery and development by identifying genetic factors that contribute to variation in disease risk as well as drug pharmacokinetics, treatment efficacy, and adverse drug reactions. In spite of the technological advancements, successful application in biomedical research would be limited without access to suitable sample collections. To facilitate exploratory genetics research, we have assembled a DNA resource from a large number of subjects participating in multiple studies throughout the world. This growing resource was initially genotyped with a commercially available genome-wide 500,000 single-nucleotide polymorphism panel. This project includes nearly 6,000 subjects of African-American, East Asian, South Asian, Mexican, and European origin. Seven informative axes of variation identified via principal-component analysis (PCA) of these data confirm the overall integrity of the data and highlight important features of the genetic structure of diverse populations. The potential value of such extensively genotyped collections is illustrated by selection of genetically matched population controls in a genome-wide analysis of abacavir-associated hypersensitivity reaction. We find that matching based on country of origin, identity-by-state distance, and multidimensional PCA do similarly well to control the type I error rate. The genotype and demographic data from this reference sample are freely available through the NCBI database of Genotypes and Phenotypes (dbGaP).
Full Text: View/download PDF

120. Population-Based Genome-wide Association Studies Reveal Six Loci Influencing Plasma Levels of Liver Enzymes

Author: Gérard Waeber, James Scott, Dawn M. Waterworth, Heide A. Stirnadel, Vincent Mooser, Peter Vollenweider, Xin Yuan, Weihua Zhang, Kijoung Song, John R. B. Perry, Sven Bergmann, Lon R. Cardon, Luigi Ferrucci, Yun Li, Noam D. Beckmann, Noha Lim, Jaspal S. Kooner, Timothy M. Frayling, Toby Johnson, John C. Chambers, David Melzer, Paul Elliott, Andrew B. Singleton, and Dena G. Hernandez
Subjects: Adult, Male, Candidate gene, Genotype, Genome-wide association study, Locus (genetics), Single-nucleotide polymorphism, Biology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Report, Genetics, Humans, Genetics(clinical), Gamma-glutamyltransferase, Genetics (clinical), Chromosome 12, 030304 developmental biology, Aged, 0303 health sciences, Genome, Human, ALPL, Alanine Transaminase, gamma-Glutamyltransferase, Middle Aged, Alkaline Phosphatase, Molecular biology, 3. Good health, Enzymes, Genetics, Population, Liver, biology.protein, 030211 gastroenterology & hepatology, Female, Chromosome 22
Abstract: Plasma liver-enzyme tests are widely used in the clinic for the diagnosis of liver diseases and for monitoring the response to drug treatment. There is considerable evidence that human genetic variation influences plasma levels of liver enzymes. However, such genetic variation has not been systematically assessed. In the present study, we performed a genome-wide association study of plasma liver-enzyme levels in three populations (total n = 7715) with replication in three additional cohorts (total n = 4704). We identified two loci influencing plasma levels of alanine-aminotransferase (ALT) (CPN1-ERLIN1-CHUK on chromosome 10 and PNPLA3-SAMM50 on chromosome 22), one locus influencing gamma-glutamyl transferase (GGT) levels (HNF1A on chromosome 12), and three loci for alkaline phosphatase (ALP) levels (ALPL on chromosome 1, GPLD1 on chromosome 6, and JMJD1C-REEP3 on chromosome 10). In addition, we confirmed the associations between the GGT1 locus and GGT levels and between the ABO locus and ALP levels. None of the ALP-associated SNPs were associated with other liver tests, suggesting intestine and/or bone specificity. The mechanisms underlying the associations may involve cis- or trans-transcriptional effects (some of the identified variants were associated with mRNA transcription in human liver or lymphoblastoid cells), dysfunction of the encoded proteins (caused by missense variations at the functional domains), or other unknown pathways. These findings may help in the interpretation of liver-enzyme tests and provide candidate genes for liver diseases of viral, metabolic, autoimmune, or toxic origin. The specific associations with ALP levels may point to genes for bone or intestinal diseases.
Full Text: View/download PDF

121. Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author: Dragana Vuckovic, Mariaelisa Graff, M. Arfan Ikram, Marit E. Jørgensen, Lia E. Bang, Gerome Breen, Torben Jørgensen, Matthias Blüher, Ivan Brandslund, Hester M. den Ruijter, Ian Ford, Timo A. Lakka, Jennifer Wessel, J. Wouter Jukema, Adam S. Butterworth, Iris M. Heid, Xiuqing Guo, Shuai Wang, Paul L. Auer, Tamuno Alfred, Katja K.H. Aben, Inês Barroso, Gail Davies, Helen Griffiths, Heather M. Highland, Myriam Fornage, Claudia Langenberg, Daniel R. Witte, Ilaria Gandin, Kent D. Taylor, Patrick T. Ellinor, Matti Uusitupa, Laura M. Yerges-Armstrong, Fotios Drenos, Lars Wallentin, Joanna M. M. Howson, Jaakko Tuomilehto, Andrew D. Morris, Lawrence F. Bielak, Mengmeng Du, Andrew J. Lotery, Ailith Pirie, Francis S. Collins, Eva Rabing Brix Petersen, Carolina Medina-Gomez, Manuel A. Rivas, Maria Karaleftheri, Jan-Håkan Jansson, Peter Kovacs, Jaspal S. Kooner, Markku Laakso, Fredrik Karpe, Markus Perola, Anubha Mahajan, Heather M. Stringham, Rohit Varma, Alex W. Hewitt, Chris J. Packard, Andrew C. Heath, Claudia Schurmann, Nele Friedrich, David Lamparter, Vanisha Mistry, Renée de Mutsert, Unnur Thorsteinsdottir, Naveed Sattar, Jennifer E. Huffman, Dale R. Nyholt, Johanna Kuusisto, Angela L. Mazul, Hanieh Yaghootkar, George Dedoussis, Yadav Sapkota, Elizabeth K. Speliotes, Amanda J. Cox, Jane Gibson, Christian Theil Have, Penny Gordon-Larsen, Alisa K. Manning, Jaakko Kaprio, Sita H. Vermeulen, Stella Trompet, Yucheng Jia, Dennis O. Mook-Kanamori, Torben Hansen, Kathleen Stirrups, Jean Ferrières, Douglas F. Easton, Ruth J. F. Loos, Gerard Pasterkamp, John M. Starr, Tellervo Korhonen, Betina H. Thuesen, Olov Rolandsson, Veikko Salomaa, Eric B. Larson, Thomas F. Vogt, John Danesh, Honghuang Lin, Gaëlle Marenne, Timothy M. Frayling, Anette Varbo, Daniel I. Chasman, Aliki-Eleni Farmaki, Lorraine Southam, Martina Müller-Nurasyid, Katharine R. Owen, Paul Mitchell, Ching-Ti Liu, Massimiliano Cocca, Anette P. Gjesing, Charles Kooperberg, Rebecca S. Fine, Wei Gan, Amy J. Swift, Gerard Tromp, Krina T. Zondervan, Henrik Vestergaard, Katherine S. Ruth, Angela D'Eustacchio, Uwe Völker, Beverley Balkau, Hayato Tada, Ingrid B. Borecki, Xueling Sim, Gudmar Thorleifsson, Wei Zhou, Yiqin Wang, Eleftheria Zeggini, Cora E. Lewis, Michael Boehnke, Evangelos Evangelou, Gabriel Cuellar-Partida, Sven Bergmann, Tinca J. C. Polderman, Philippe Amouyel, Roberta McKean-Cowdin, Ellen W. Demerath, Marco Brumat, Kjell Nikus, Anneke I den Hollander, Stefan Gustafsson, Allan Linneberg, Peter T. Campbell, Weihua Zhang, Leslie A. Lange, Gina M. Peloso, Jonathan P. Bradfield, Cornelia M. van Duijn, Xiaowei Zhan, Marie-Pierre Dubé, Liang He, André G. Uitterlinden, Anne Tybjærg-Hansen, Yingchang Lu, Wei Zhao, Liang Sun, Yii-Der Ida Chen, Paul I. W. de Bakker, Børge G. Nordestgaard, Karina Meidtner, Carsten A. Böger, Lynne E. Wagenknecht, Eric Kim, Pang Yao, Olli T. Raitakari, Nanette R. Lee, René S. Kahn, Lili Milani, Tessel E. Galesloot, Jussi Hernesniemi, Valgerdur Steinthorsdottir, Jie Yao, Eulalia Catamo, Kerrin S. Small, Sara M. Willems, Marcelo P. Segura-Lepe, Cecilia M. Lindgren, Asif Rasheed, Gonçalo R. Abecasis, Adam E. Locke, Konstantin Strauch, Albert V. Smith, Anke R. Hammerschlag, Frida Renström, Zoltán Kutalik, Giovanni Veronesi, Paul M. Ridker, David J. Carey, Yao Hu, Jaana Lindström, John Andrew Pospisilik, Mike A. Nalls, Erik Ingelsson, Colin N. A. Palmer, Mary F. Feitosa, John R. B. Perry, Anne E. Justice, Ele Ferrannini, Shuang Feng, Helen R. Warren, David J. Roberts, Igor Rudan, Jeffrey R. O'Connel, Alison Pattie, Christopher P. Nelson, Lars Lind, Feijie Wang, Tamara B. Harris, Keng-Hung Lin, Jerome I. Rotter, Matthew A. Allison, Robin Young, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Stefan Johansson, Alexander P. Reiner, Jing Hua Zhao, Poorva Mudgal, Tim D. Spector, Paul W. Franks, Loes M. Olde Loohuis, Harvey D. White, Pirjo Komulainen, Michelle L. O'Donoghue, Todd L. Edwards, Ozren Polasek, Andrew R. Wood, Dermot F. Reilly, Myriam Rheinberger, Cramer Christensen, G. Kees Hovingh, Hidetoshi Kitajima, Kristin L. Young, Audrey Y. Chu, Megan L. Grove, Suthesh Sivapalaratnam, Lisa Bastarache, Martin den Heijer, Oddgeir L. Holmen, Vilmundur Gudnason, Sameer E. Al-Harthi, Dewan S. Alam, Robert E. Schoen, Jin Li, Sascha Fauser, Janie Corley, Paolo Gasparini, Niels Grarup, Guillaume Lettre, Thomas N. Person, Mark I. McCarthy, Joel N. Hirschhorn, Ying Wu, Pia R. Kamstrup, Nilesh J. Samani, Panos Deloukas, Ethan M. Lange, Helena Kuivaniemi, Mika Kähönen, Michiel L. Bots, Annette Peters, Peggy L. Peissig, Wayne Huey-Herng Sheu, Steven A. Lubitz, Stefania Cappellani, Mauno Vanhala, Andrew P. Morris, Struan F.A. Grant, Mark Walker, Trevor A. Mori, Jian'an Luan, Matthias B. Schulze, Josh C. Denny, Sarah E. Medland, Sander W. van der Laan, Maggie C.Y. Ng, Eric Boerwinkle, Tibor V. Varga, Øyvind Helgeland, Anke Tönjes, Jessica van Setten, James P. Cook, Patricia B. Munroe, Heiner Boeing, Robert A. Scott, Karen L. Mohlke, Leena Moilanen, Ayush Giri, Andrew J. Slater, Andrew T. Hattersley, Mark J. Caulfield, Tõnu Esko, Mark C. H. Groot, Nancy L. Heard-Costa, Narisu Narisu, Danish Saleheen, Valérie Turcot, Lambertus A. Kiemeney, Nicholas G. D. Masca, Ruifang Li-Gao, Jean-Claude Tardif, Xu Lin, Kathleen Mullan Harris, Antonietta Robino, Alison M. Dunning, Jonathan Tyrer, Audrey E. Hendricks, Linda Broer, Patricia A. Peyser, Jessica D. Faul, Jose C. Florez, Anne U. Jackson, Eirini Marouli, Jette Bork-Jensen, John C. Chambers, Jordi Corominas Galbany, Ruth Frikke-Schmidt, David S. Crosslin, Bratati Kahali, Stavroula Kanoni, Gorm B. Jensen, Nicholas J. Wareham, Paul Elliott, Tune H. Pers, James A. Perry, Tugce Karaderi, Matt J. Neville, Marianne Benn, Svati H. Shah, Mathias Gorski, Michael Stumvoll, David Ellinghaus, Amber A. Burt, Kari E. North, Jeffrey Haessler, Rajiv Chowdhury, Folkert W. Asselbergs, Marie Moitry, Aniruddh P. Patel, Pamela J. Schreiner, Frank Kee, Donald W. Bowden, Sune F. Nielsen, Oluf Pedersen, John D. Rioux, Rainer Rauramaa, Satu Männistö, Deborah J. Thompson, Cristen J. Willer, Andre Franke, Kari Kuulasmaa, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Sekar Kathiresan, Erin B. Ware, Dawn M. Waterworth, James G. Wilson, Sandosh Padmanabhan, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Digna R. Velez Edwards, Artitaya Lophatananon, Craig E. Pennell, Gail P. Jarvik, Adelheid Lempradl, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Oscar H. Franco, Yongmei Liu, I. Sadaf Farooqi, Hannu Puolijoki, Huaixing Li, Caroline Hayward, Rudolf Uher, Veronique Vitart, Murray H. Brilliant, Kari Stefansson, Alexander Teumer, Nicholette D. Palmer, Vilmantas Giedraitis, Roel A. Ophoff, Sailaja Vedantam, Emanuele Di Angelantonio, Ken S. Lo, Grant W. Montgomery, Paul L. Huang, Praveen Surendran, Terho Lehtimäki, Katherine E. Tansey, Li-An Lin, Pål R. Njølstad, Thomas W. Winkler, Ian J. Deary, Erwin P. Bottinger, Carol A. Wang, Biological Psychology, Complex Trait Genetics, and Amsterdam Neuroscience - Complex Trait Genetics
Subjects: 0301 basic medicine, 2. Zero hunger, 0303 health sciences, ComputerSystemsOrganization_COMPUTERSYSTEMIMPLEMENTATION, Published Erratum, Computational biology, Biology, medicine.disease, Obesity, Genealogy, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, ddc:570, Genetics, medicine, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Biological sciences, Body mass index, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.
Full Text: View/download PDF

122. Identification and validation of copy number variants using SNP genotyping arrays from a large clinical cohort

Author: Jacques S. Beckmann, Brian Stevenson, Peter Vollenweider, Vincent Mooser, Sven Bergmann, Dawn M. Waterworth, C. Victor Jongeneel, Armand Valsesia, Zoltán Kutalik, and Gérard Waeber
Subjects: lcsh:QH426-470, DNA Copy Number Variations, Genotype, lcsh:Biotechnology, Population, Normal Distribution, Genome-wide association study, Computational biology, Biology, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, lcsh:TP248.13-248.65, Genetics, Humans, SNP, Copy-number variation, education, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, Genetic association, Principal Component Analysis, 0303 health sciences, education.field_of_study, Genome, Human, SNP genotyping, lcsh:Genetics, Human genome, Algorithms, 030217 neurology & neurosurgery, Research Article, Genome-Wide Association Study, Biotechnology
Abstract: Background Genotypes obtained with commercial SNP arrays have been extensively used in many large case-control or population-based cohorts for SNP-based genome-wide association studies for a multitude of traits. Yet, these genotypes capture only a small fraction of the variance of the studied traits. Genomic structural variants (GSV) such as Copy Number Variation (CNV) may account for part of the missing heritability, but their comprehensive detection requires either next-generation arrays or sequencing. Sophisticated algorithms that infer CNVs by combining the intensities from SNP-probes for the two alleles can already be used to extract a partial view of such GSV from existing data sets. Results Here we present several advances to facilitate the latter approach. First, we introduce a novel CNV detection method based on a Gaussian Mixture Model. Second, we propose a new algorithm, PCA merge, for combining copy-number profiles from many individuals into consensus regions. We applied both our new methods as well as existing ones to data from 5612 individuals from the CoLaus study who were genotyped on Affymetrix 500K arrays. We developed a number of procedures in order to evaluate the performance of the different methods. This includes comparison with previously published CNVs as well as using a replication sample of 239 individuals, genotyped with Illumina 550K arrays. We also established a new evaluation procedure that employs the fact that related individuals are expected to share their CNVs more frequently than randomly selected individuals. The ability to detect both rare and common CNVs provides a valuable resource that will facilitate association studies exploring potential phenotypic associations with CNVs. Conclusion Our new methodologies for CNV detection and their evaluation will help in extracting additional information from the large amount of SNP-genotyping data on various cohorts and use this to explore structural variants and their impact on complex traits.
Full Text: View/download PDF

123. Phenome-wide association study using research participants' self-reported data provides insight into the Th17 and IL-17 pathway.

Author: Margaret G Ehm, Jennifer L Aponte, Mathias N Chiano, Laura M Yerges-Armstrong, Toby Johnson, Jonathan N Barker, Suzanne F Cook, Akanksha Gupta, David A Hinds, Li Li, Matthew R Nelson, Michael A Simpson, Chao Tian, Linda C McCarthy, Deepak K Rajpal, and Dawn M Waterworth
Subjects: Medicine, Science
Abstract: A phenome-wide association study of variants in genes in the Th17 and IL-17 pathway was performed using self-reported phenotypes and genetic data from 521,000 research participants of 23andMe. Results replicated known associations with similar effect sizes for autoimmune traits illustrating self-reported traits can be a surrogate for clinically assessed conditions. Novel associations controlling for a false discovery rate of 5% included the association of the variant encoding p.Ile684Ser in TYK2 with increased risk of tonsillectomy, strep throat occurrences and teen acne, the variant encoding p.Arg381Gln in IL23R with a decrease in dandruff frequency, the variant encoding p.Asp10Asn in TRAF3IP2 with risk of male-pattern balding, and the RORC regulatory variant (rs4845604) with protection from allergies. This approach enabled rapid assessment of association with a wide variety of traits and investigation of traits with limited reported associations to overlay meaningful phenotypic context on the range of conditions being considered for drugs targeting this pathway.
Published: 2017
Full Text: View/download PDF

124. Genome-wide association study of metabolic traits reveals novel gene-metabolite-disease links.

Author: Rico Rueedi, Mirko Ledda, Andrew W Nicholls, Reza M Salek, Pedro Marques-Vidal, Edgard Morya, Koichi Sameshima, Ivan Montoliu, Laeticia Da Silva, Sebastiano Collino, François-Pierre Martin, Serge Rezzi, Christoph Steinbeck, Dawn M Waterworth, Gérard Waeber, Peter Vollenweider, Jacques S Beckmann, Johannes Le Coutre, Vincent Mooser, Sven Bergmann, Ulrich K Genick, and Zoltán Kutalik
Subjects: Genetics, QH426-470
Abstract: Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on (1)H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P
Published: 2014
Full Text: View/download PDF

125. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Author: Zari Dastani, Marie-France Hivert, Nicholas Timpson, John R B Perry, Xin Yuan, Robert A Scott, Peter Henneman, Iris M Heid, Jorge R Kizer, Leo-Pekka Lyytikäinen, Christian Fuchsberger, Toshiko Tanaka, Andrew P Morris, Kerrin Small, Aaron Isaacs, Marian Beekman, Stefan Coassin, Kurt Lohman, Lu Qi, Stavroula Kanoni, James S Pankow, Hae-Won Uh, Ying Wu, Aurelian Bidulescu, Laura J Rasmussen-Torvik, Celia M T Greenwood, Martin Ladouceur, Jonna Grimsby, Alisa K Manning, Ching-Ti Liu, Jaspal Kooner, Vincent E Mooser, Peter Vollenweider, Karen A Kapur, John Chambers, Nicholas J Wareham, Claudia Langenberg, Rune Frants, Ko Willems-Vandijk, Ben A Oostra, Sara M Willems, Claudia Lamina, Thomas W Winkler, Bruce M Psaty, Russell P Tracy, Jennifer Brody, Ida Chen, Jorma Viikari, Mika Kähönen, Peter P Pramstaller, David M Evans, Beate St Pourcain, Naveed Sattar, Andrew R Wood, Stefania Bandinelli, Olga D Carlson, Josephine M Egan, Stefan Böhringer, Diana van Heemst, Lyudmyla Kedenko, Kati Kristiansson, Marja-Liisa Nuotio, Britt-Marie Loo, Tamara Harris, Melissa Garcia, Alka Kanaya, Margot Haun, Norman Klopp, H-Erich Wichmann, Panos Deloukas, Efi Katsareli, David J Couper, Bruce B Duncan, Margreet Kloppenburg, Linda S Adair, Judith B Borja, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, James G Wilson, Solomon Musani, Xiuqing Guo, Toby Johnson, Robert Semple, Tanya M Teslovich, Matthew A Allison, Susan Redline, Sarah G Buxbaum, Karen L Mohlke, Ingrid Meulenbelt, Christie M Ballantyne, George V Dedoussis, Frank B Hu, Yongmei Liu, Bernhard Paulweber, Timothy D Spector, P Eline Slagboom, Luigi Ferrucci, Antti Jula, Markus Perola, Olli Raitakari, Jose C Florez, Veikko Salomaa, Johan G Eriksson, Timothy M Frayling, Andrew A Hicks, Terho Lehtimäki, George Davey Smith, David S Siscovick, Florian Kronenberg, Cornelia van Duijn, Ruth J F Loos, Dawn M Waterworth, James B Meigs, Josee Dupuis, J Brent Richards, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Oliver M Hofmann, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stephane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Andrew D Morris, Colin N A Palmer, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Richard M Watanabe, Goncalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Oluf Pedersen, Inês Barroso, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Paul Elliott, Denis Rybin, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Taina Lajunen, Alex Doney, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jerome Delplanque, Annette C Fedson, Antje Fischer-Rosinsky, Nita G Forouhi, Maria Grazia Franzosi, Pilar Galan, Mark O Goodarzi, Jürgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesaniemi, Mika Kivimaki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Andreas F H Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Gunnar Sigurðsson, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Ingrid B Borecki, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Procardis Consortium, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, Brenda W J H Penninx, Dorret I Boomsma, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Leena Peltonen, Vincent Mooser, Robert Sladek, MAGIC investigators, GLGC Consortium, Kiran Musunuru, Albert V Smith, Andrew C Edmondson, Ioannis M Stylianou, Masahiro Koseki, James P Pirruccello, Daniel I Chasman, Christopher T Johansen, Sigrid W Fouchier, Gina M Peloso, Maja Barbalic, Sally L Ricketts, Joshua C Bis, Mary F Feitosa, Marju Orho-Melander, Olle Melander, Xiaohui Li, Mingyao Li, Yoon Shin Cho, Min Jin Go, Young Jin Kim, Jong-Young Lee, Taesung Park, Kyunga Kim, Xueling Sim, Rick Twee-Hee Ong, Damien C Croteau-Chonka, Leslie A Lange, Joshua D Smith, Andreas Ziegler, Weihua Zhang, Robert Y L Zee, John B Whitfield, John R Thompson, Ida Surakka, Tim D Spector, Johannes H Smit, Juha Sinisalo, James Scott, Juha Saharinen, Chiara Sabatti, Lynda M Rose, Robert Roberts, Mark Rieder, Alex N Parker, Guillaume Pare, Christopher J O'Donnell, Markku S Nieminen, Deborah A Nickerson, Grant W Montgomery, Wendy McArdle, David Masson, Nicholas G Martin, Fabio Marroni, Gavin Lucas, Robert Luben, Marja-Liisa Lokki, Guillaume Lettre, Lenore J Launer, Edward G Lakatta, Reijo Laaksonen, Kirsten O Kyvik, Inke R König, Kay-Tee Khaw, Lee M Kaplan, Åsa Johansson, A Cecile J W Janssens, Wilmar Igl, G Kees Hovingh, Christian Hengstenberg, Aki S Havulinna, Nicholas D Hastie, Tamara B Harris, Talin Haritunians, Alistair S Hall, Leif C Groop, Elena Gonzalez, Nelson B Freimer, Jeanette Erdmann, Kenechi G Ejebe, Angela Döring, Anna F Dominiczak, Serkalem Demissie, Panagiotis Deloukas, Ulf de Faire, Gabriel Crawford, Yii-der I Chen, Mark J Caulfield, S Matthijs Boekholdt, Themistocles L Assimes, Thomas Quertermous, Mark Seielstad, Tien Y Wong, E-Shyong Tai, Alan B Feranil, Christopher W Kuzawa, Herman A Taylor, Stacey B Gabriel, Hilma Holm, Vilmundur Gudnason, Ronald M Krauss, Jose M Ordovas, Patricia B Munroe, Jaspal S Kooner, Alan R Tall, Robert A Hegele, John J P Kastelein, Eric E Schadt, David P Strachan, Muredach P Reilly, Nilesh J Samani, Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, and Sekar Kathiresan
Subjects: Genetics, QH426-470
Abstract: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p
Published: 2012
Full Text: View/download PDF

126. A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol.

Author: Ida Surakka, Aaron Isaacs, Lennart C Karssen, Pirkka-Pekka P Laurila, Rita P S Middelberg, Emmi Tikkanen, Janina S Ried, Claudia Lamina, Massimo Mangino, Wilmar Igl, Jouke-Jan Hottenga, Vasiliki Lagou, Pim van der Harst, Irene Mateo Leach, Tõnu Esko, Zoltán Kutalik, Nicholas W Wainwright, Maksim V Struchalin, Antti-Pekka Sarin, Antti J Kangas, Jorma S Viikari, Markus Perola, Taina Rantanen, Ann-Kristin Petersen, Pasi Soininen, Asa Johansson, Nicole Soranzo, Andrew C Heath, Theodore Papamarkou, Inga Prokopenko, Anke Tönjes, Florian Kronenberg, Angela Döring, Fernando Rivadeneira, Grant W Montgomery, John B Whitfield, Mika Kähönen, Terho Lehtimäki, Nelson B Freimer, Gonneke Willemsen, Eco J C de Geus, Aarno Palotie, Manj S Sandhu, Dawn M Waterworth, Andres Metspalu, Michael Stumvoll, André G Uitterlinden, Antti Jula, Gerjan Navis, Cisca Wijmenga, Bruce H R Wolffenbuttel, Marja-Riitta Taskinen, Mika Ala-Korpela, Jaakko Kaprio, Kirsten O Kyvik, Dorret I Boomsma, Nancy L Pedersen, Ulf Gyllensten, James F Wilson, Igor Rudan, Harry Campbell, Peter P Pramstaller, Tim D Spector, Jacqueline C M Witteman, Johan G Eriksson, Veikko Salomaa, Ben A Oostra, Olli T Raitakari, H-Erich Wichmann, Christian Gieger, Marjo-Riitta Järvelin, Nicholas G Martin, Albert Hofman, Mark I McCarthy, Leena Peltonen, Cornelia M van Duijn, Yurii S Aulchenko, Samuli Ripatti, and ENGAGE Consortium
Subjects: Genetics, QH426-470
Abstract: Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
Published: 2011
Full Text: View/download PDF

127. Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.

Author: Cecilia M Lindgren, Iris M Heid, Joshua C Randall, Claudia Lamina, Valgerdur Steinthorsdottir, Lu Qi, Elizabeth K Speliotes, Gudmar Thorleifsson, Cristen J Willer, Blanca M Herrera, Anne U Jackson, Noha Lim, Paul Scheet, Nicole Soranzo, Najaf Amin, Yurii S Aulchenko, John C Chambers, Alexander Drong, Jian'an Luan, Helen N Lyon, Fernando Rivadeneira, Serena Sanna, Nicholas J Timpson, M Carola Zillikens, Jing Hua Zhao, Peter Almgren, Stefania Bandinelli, Amanda J Bennett, Richard N Bergman, Lori L Bonnycastle, Suzannah J Bumpstead, Stephen J Chanock, Lynn Cherkas, Peter Chines, Lachlan Coin, Cyrus Cooper, Gabriel Crawford, Angela Doering, Anna Dominiczak, Alex S F Doney, Shah Ebrahim, Paul Elliott, Michael R Erdos, Karol Estrada, Luigi Ferrucci, Guido Fischer, Nita G Forouhi, Christian Gieger, Harald Grallert, Christopher J Groves, Scott Grundy, Candace Guiducci, David Hadley, Anders Hamsten, Aki S Havulinna, Albert Hofman, Rolf Holle, John W Holloway, Thomas Illig, Bo Isomaa, Leonie C Jacobs, Karen Jameson, Pekka Jousilahti, Fredrik Karpe, Johanna Kuusisto, Jaana Laitinen, G Mark Lathrop, Debbie A Lawlor, Massimo Mangino, Wendy L McArdle, Thomas Meitinger, Mario A Morken, Andrew P Morris, Patricia Munroe, Narisu Narisu, Anna Nordström, Peter Nordström, Ben A Oostra, Colin N A Palmer, Felicity Payne, John F Peden, Inga Prokopenko, Frida Renström, Aimo Ruokonen, Veikko Salomaa, Manjinder S Sandhu, Laura J Scott, Angelo Scuteri, Kaisa Silander, Kijoung Song, Xin Yuan, Heather M Stringham, Amy J Swift, Tiinamaija Tuomi, Manuela Uda, Peter Vollenweider, Gerard Waeber, Chris Wallace, G Bragi Walters, Michael N Weedon, Wellcome Trust Case Control Consortium, Jacqueline C M Witteman, Cuilin Zhang, Weihua Zhang, Mark J Caulfield, Francis S Collins, George Davey Smith, Ian N M Day, Paul W Franks, Andrew T Hattersley, Frank B Hu, Marjo-Riitta Jarvelin, Augustine Kong, Jaspal S Kooner, Markku Laakso, Edward Lakatta, Vincent Mooser, Andrew D Morris, Leena Peltonen, Nilesh J Samani, Timothy D Spector, David P Strachan, Toshiko Tanaka, Jaakko Tuomilehto, André G Uitterlinden, Cornelia M van Duijn, Nicholas J Wareham, Hugh Watkins, Procardis Consortia, Dawn M Waterworth, Michael Boehnke, Panos Deloukas, Leif Groop, David J Hunter, Unnur Thorsteinsdottir, David Schlessinger, H-Erich Wichmann, Timothy M Frayling, Gonçalo R Abecasis, Joel N Hirschhorn, Ruth J F Loos, Kari Stefansson, Karen L Mohlke, Inês Barroso, Mark I McCarthy, and Giant Consortium
Subjects: Genetics, QH426-470
Abstract: To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
Published: 2009
Full Text: View/download PDF

128. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Author: Wessel, Jennifer, Chu, Audrey Y, Willems, Sara M, Wang, Shuai, Yaghootkar, Hanieh, Brody, Jennifer A, Dauriz, Marco, Hivert, Marie-France, Raghavan, Sridharan, Lipovich, Leonard, Hidalgo, Bertha, Fox, Keolu, Huffman, Jennifer E, An, Ping, Lu, Yingchang, Rasmussen-Torvik, Laura J, Grarup, Niels, Ehm, Margaret G, Li, Li, Baldridge, Abigail S, Stančáková, Alena, Abrol, Ravinder, Besse, Céline, Boland, Anne, Bork-Jensen, Jette, Fornage, Myriam, Freitag, Daniel F, Garcia, Melissa E, Guo, Xiuqing, Hara, Kazuo, Isaacs, Aaron, Jakobsdottir, Johanna, Lange, Leslie A, Layton, Jill C, Li, Man, Hua Zhao, Jing, Meidtner, Karina, Morrison, Alanna C, Nalls, Mike A, Peters, Marjolein J, Sabater-Lleal, Maria, Schurmann, Claudia, Silveira, Angela, Smith, Albert V, Southam, Lorraine, Stoiber, Marcus H, Strawbridge, Rona J., Taylor, Kent D, Varga, Tibor V, Allin, Kristine H, Amin, Najaf, Aponte, Jennifer L, Aung, Tin, Barbieri, Caterina, Bihlmeyer, Nathan A, Boehnke, Michael, Bombieri, Cristina, Bowden, Donald W, Burns, Sean M, Chen, Yuning, Chen, Yii-DerI, Cheng, Ching-Yu, Correa, Adolfo, Czajkowski, Jacek, Dehghan, Abbas, Ehret, Georg B, Eiriksdottir, Gudny, Escher, Stefan A, Farmaki, Aliki-Eleni, Frånberg, Mattias, Gambaro, Giovanni, Giulianini, Franco, Goddard, William A, Goel, Anuj, Gottesman, Omri, Grove, Megan L, Gustafsson, Stefan, Hai, Yang, Hallmans, Göran, Heo, Jiyoung, Hoffmann, Per, Ikram, Mohammad K, Jensen, Richard A, Jørgensen, Marit E, Jørgensen, Torben, Karaleftheri, Maria, Khor, Chiea C, Kirkpatrick, Andrea, Kraja, Aldi T, Kuusisto, Johanna, Lange, Ethan M, Lee, I T, Lee, Wen-Jane, Leong, Aaron, Liao, Jiemin, Liu, Chunyu, Liu, Yongmei, Lindgren, Cecilia M, Linneberg, Allan, Malerba, Giovanni, Mamakou, Vasiliki, Marouli, Eirini, Maruthur, Nisa M, Matchan, Angela, McKean-Cowdin, Roberta, McLeod, Olga, Metcalf, Ginger A, Mohlke, Karen L, Muzny, Donna M, Ntalla, Ioanna, Palmer, Nicholette D, Pasko, Dorota, Peter, Andreas, Rayner, Nigel W, Renström, Frida, Rice, Ken, Sala, Cinzia F, Sennblad, Bengt, Serafetinidis, Ioannis, Smith, Jennifer A, Soranzo, Nicole, Speliotes, Elizabeth K, Stahl, Eli A, Stirrups, Kathleen, Tentolouris, Nikos, Thanopoulou, Anastasia, Torres, Mina, Traglia, Michela, Tsafantakis, Emmanouil, Javad, Sundas, Yanek, Lisa R, Zengini, Eleni, Becker, Diane M, Bis, Joshua C, Brown, James B, Adrienne Cupples, L, Hansen, Torben, Ingelsson, Erik, Karter, Andrew J, Lorenzo, Carlos, Mathias, Rasika A, Norris, Jill M, Peloso, Gina M, Sheu, Wayne H.-H., Toniolo, Daniela, Vaidya, Dhananjay, Varma, Rohit, Wagenknecht, Lynne E, Boeing, Heiner, Bottinger, Erwin P, Dedoussis, George, Deloukas, Panos, Ferrannini, Ele, Franco, Oscar H, Franks, Paul W, Gibbs, Richard A, Gudnason, Vilmundur, Hamsten, Anders, Harris, Tamara B, Hattersley, Andrew T, Hayward, Caroline, Hofman, Albert, Jansson, Jan-Håkan, Langenberg, Claudia, Launer, Lenore J, Levy, Daniel, Oostra, Ben A, O’Donnell, Christopher J, O’Rahilly, Stephen, Padmanabhan, Sandosh, Pankow, James S, Polasek, Ozren, Province, Michael A, Rich, Stephen S, Ridker, Paul M, Rudan, Igor, Schulze, Matthias B, Smith, Blair H, Uitterlinden, André G, Walker, Mark, Watkins, Hugh, Wong, Tien Y, Zeggini, Eleftheria, Sharp, Stephen J, Forouhi, Nita G, Kerrison, Nicola D, Lucarelli, Debora ME, Sims, Matt, Barroso, Inês, McCarthy, Mark I, Arriola, Larraitz, Balkau, Beverley, Barricarte, Aurelio, Gonzalez, Carlos, Grioni, Sara, Kaaks, Rudolf, Key, Timothy J, Navarro, Carmen, Nilsson, Peter M, Overvad, Kim, Palli, Domenico, Panico, Salvatore, Quirós, J. Ramón, Rolandsson, Olov, Sacerdote, Carlotta, Sánchez, María–José, Slimani, Nadia, Tjonneland, Anne, Tumino, Rosario, van der A, Daphne L, van der Schouw, Yvonne T, Riboli, Elio, Laakso, Markku, Borecki, Ingrid B, Chasman, Daniel I, Pedersen, Oluf, Psaty, Bruce M, Shyong Tai, E, van Duijn, Cornelia M, Wareham, Nicholas J, Waterworth, Dawn M, Boerwinkle, Eric, Linda Kao, W H, Florez, Jose C, Loos, Ruth J.F., Wilson, James G, Frayling, Timothy M, Siscovick, David S, Dupuis, Josée, Rotter, Jerome I, Meigs, James B, Scott, Robert A, Goodarzi, Mark O, Jennifer Wessel, Audrey Y. Chu, Sara M. Willems, Shuai Wang, Hanieh Yaghootkar, Jennifer A. Brody, Marco Dauriz, Marie France Hivert, Sridharan Raghavan, Leonard Lipovich, Bertha Hidalgo, Keolu Fox, Jennifer E. Huffman, Ping An, Yingchang Lu, Laura J. Rasmussen Torvik, Niels Grarup, Margaret G. Ehm, Li Li, Abigail S. Baldridge, Alena Stančáková, Ravinder Abrol, Céline Besse, Anne Boland, Jette Bork Jensen, Myriam Fornage, Daniel F. Freitag, Melissa E. Garcia, Xiuqing Guo, Kazuo Hara, Aaron Isaacs, Johanna Jakobsdottir, Leslie A. Lange, Jill C. Layton, Man Li, Jing Hua Zhao, Karina Meidtner, Alanna C. Morrison, Mike A. Nalls, Marjolein J. Peter, Maria Sabater Lleal, Claudia Schurmann, Angela Silveira, Albert V. Smith, Lorraine Southam, Marcus H. Stoiber, Rona J. Strawbridge, Kent D. Taylor, Tibor V. Varga, Kristine H. Allin, Najaf Amin, Jennifer L. Aponte, Tin, Aung, Barbieri, CATERINA MARIA, Nathan A. Bihlmeyer, Michael Boehnke, Cristina Bombieri, Donald W. Bowden, Sean M. Burns, Yuning Chen, Yii DerI Chen, Ching Yu Cheng, Adolfo Correa, Jacek Czajkowski, Abbas Dehghan, Georg B. Ehret, Gudny Eiriksdottir, Stefan A. Escher, Aliki Eleni Farmaki, Mattias Frånberg, Giovanni Gambaro, Franco Giulianini, William A. Goddard, Anuj Goel, Omri Gottesman, Megan L. Grove, Stefan Gustafsson, Yang Hai, Göran Hallmans, Jiyoung Heo, Per Hoffmann, Mohammad K. Ikram, Richard A. Jensen, Marit E. Jørgensen, Torben Jørgensen, Maria Karaleftheri, Chiea C. Khor, Andrea Kirkpatrick, Aldi T. Kraja, Johanna Kuusisto, Ethan M. Lange, I. T. Lee, Wen Jane Lee, Aaron Leong, Jiemin Liao, Chunyu Liu, Yongmei Liu, Cecilia M. Lindgren, Allan Linneberg, Giovanni Malerba, Vasiliki Mamakou, Eirini Marouli, Nisa M. Maruthur, Angela Matchan, Roberta McKean Cowdin, Olga McLeod, Ginger A. Metcalf, Karen L. Mohlke, Donna M. Muzny, Ioanna Ntalla, Nicholette D. Palmer, Dorota Pasko, Andreas Peter, Nigel W. Rayner, Frida Renström, Ken Rice, Cinzia F. Sala, Bengt Sennblad, Ioannis Serafetinidis, Jennifer A. Smith, Nicole Soranzo, Elizabeth K. Speliote, Eli A. Stahl, Kathleen Stirrup, Nikos Tentolouris, Anastasia Thanopoulou, Mina Torres, Michela Traglia, Emmanouil Tsafantakis, Sundas Javad, Lisa R. Yanek, Eleni Zengini, Diane M. Becker, Joshua C. Bi, James B. Brown, L. Adrienne Cupple, Torben Hansen, Erik Ingelsson, Andrew J. Karter, Carlos Lorenzo, Rasika A. Mathias, Jill M. Norri, Gina M. Peloso, Wayne H. H. Sheu, Daniela Toniolo, Dhananjay Vaidya, Rohit Varma, Lynne E. Wagenknecht, Heiner Boeing, Erwin P. Bottinger, George Dedoussis, Panos Delouka, Ele Ferrannini, Oscar H. Franco, Paul W. Franks, Richard A. Gibb, Vilmundur Gudnason, Anders Hamsten, Tamara B. Harris, Andrew T. Hattersley, Caroline Hayward, Albert Hofman, Jan Håkan Jansson, Claudia Langenberg, Lenore J. Launer, Daniel Levy, Ben A. Oostra, Christopher J. O’Donnell, Stephen O’Rahilly, Sandosh Padmanabhan, James S. Pankow, Ozren Polasek, Michael A. Province, Stephen S. Rich, Paul M. Ridker, Igor Rudan, Matthias B. Schulze, Blair H. Smith, André G. Uitterlinden, Mark Walker, Hugh Watkins, Tien Y. Wong, Eleftheria Zeggini, The EPIC InterAct Consortium, Markku Laakso, Ingrid B. Borecki, Daniel I. Chasman, Oluf Pedersen, Bruce M. Psaty, E. Shyong Tai, Cornelia M. van Duijn, Nicholas J. Wareham, Dawn M. Waterworth, Eric Boerwinkle, W. H. Linda Kao, Jose C. Florez, Ruth J. F. Loos, James G. Wilson, Timothy M. Frayling, David S. Siscovick, Josée Dupuis, Jerome I. Rotter, James B. Meigs, Robert A. Scott, Mark O., Goodarzi, Wessel, Jennifer, Chu, Audrey Y, Willems, Sara M, Wang, Shuai, Yaghootkar, Hanieh, Brody, Jennifer A, Dauriz, Marco, Hivert, Marie France, Raghavan, Sridharan, Lipovich, Leonard, Hidalgo, Bertha, Fox, Keolu, Huffman, Jennifer E, An, Ping, Lu, Yingchang, Rasmussen Torvik, Laura J, Grarup, Niel, Ehm, Margaret G, Li, Li, Baldridge, Abigail S, Stančáková, Alena, Abrol, Ravinder, Besse, Céline, Boland, Anne, Bork Jensen, Jette, Fornage, Myriam, Freitag, Daniel F, Garcia, Melissa E, Guo, Xiuqing, Hara, Kazuo, Isaacs, Aaron, Jakobsdottir, Johanna, Lange, Leslie A, Layton, Jill C, Li, Man, Hua Zhao, Jing, Meidtner, Karina, Morrison, Alanna C, Nalls, Mike A, Peters, Marjolein J, Sabater Lleal, Maria, Schurmann, Claudia, Silveira, Angela, Smith, Albert V, Southam, Lorraine, Stoiber, Marcus H, Strawbridge, Rona J, Taylor, Kent D, Varga, Tibor V, Allin, Kristine H, Amin, Najaf, Aponte, Jennifer L, Aung, Tin, Barbieri, Caterina, Bihlmeyer, Nathan A, Boehnke, Michael, Bombieri, Cristina, Bowden, Donald W, Burns, Sean M, Chen, Yuning, Chen, Yii DerI, Cheng, Ching Yu, Correa, Adolfo, Czajkowski, Jacek, Dehghan, Abba, Ehret, Georg B, Eiriksdottir, Gudny, Escher, Stefan A, Farmaki, Aliki Eleni, Frånberg, Mattia, Gambaro, Giovanni, Giulianini, Franco, Goddard, William A, Goel, Anuj, Gottesman, Omri, Grove, Megan L, Gustafsson, Stefan, Hai, Yang, Hallmans, Göran, Heo, Jiyoung, Hoffmann, Per, Ikram, Mohammad K, Jensen, Richard A, Jørgensen, Marit E, Jørgensen, Torben, Karaleftheri, Maria, Khor, Chiea C, Kirkpatrick, Andrea, Kraja, Aldi T, Kuusisto, Johanna, Lange, Ethan M, Lee, I. T, Lee, Wen Jane, Leong, Aaron, Liao, Jiemin, Liu, Chunyu, Liu, Yongmei, Lindgren, Cecilia M, Linneberg, Allan, Malerba, Giovanni, Mamakou, Vasiliki, Marouli, Eirini, Maruthur, Nisa M, Matchan, Angela, McKean Cowdin, Roberta, Mcleod, Olga, Metcalf, Ginger A, Mohlke, Karen L, Muzny, Donna M, Ntalla, Ioanna, Palmer, Nicholette D, Pasko, Dorota, Peter, Andrea, Rayner, Nigel W, Renström, Frida, Rice, Ken, Sala, Cinzia F, Sennblad, Bengt, Serafetinidis, Ioanni, Smith, Jennifer A, Soranzo, Nicole, Speliotes, Elizabeth K, Stahl, Eli A, Stirrups, Kathleen, Tentolouris, Niko, Thanopoulou, Anastasia, Torres, Mina, Traglia, Michela, Tsafantakis, Emmanouil, Javad, Sunda, Yanek, Lisa R, Zengini, Eleni, Becker, Diane M, Bis, Joshua C, Brown, James B, Cupples, L. Adrienne, Hansen, Torben, Ingelsson, Erik, Karter, Andrew J, Lorenzo, Carlo, Mathias, Rasika A, Norris, Jill M, Peloso, Gina M, Sheu, Wayne H. H, Toniolo, Daniela, Vaidya, Dhananjay, Varma, Rohit, Wagenknecht, Lynne E, Boeing, Heiner, Bottinger, Erwin P, Dedoussis, George, Deloukas, Pano, Ferrannini, Ele, Franco, Oscar H, Franks, Paul W, Gibbs, Richard A, Gudnason, Vilmundur, Hamsten, Ander, Harris, Tamara B, Hattersley, Andrew T, Hayward, Caroline, Hofman, Albert, Jansson, Jan Håkan, Langenberg, Claudia, Launer, Lenore J, Levy, Daniel, Oostra, Ben A, O'Donnell, Christopher J, O'Rahilly, Stephen, Padmanabhan, Sandosh, Pankow, James S, Polasek, Ozren, Province, Michael A, Rich, Stephen S, Ridker, Paul M, Rudan, Igor, Schulze, Matthias B, Smith, Blair H, Uitterlinden, André G, Walker, Mark, Watkins, Hugh, Wong, Tien Y, Zeggini, Eleftheria, Laakso, Markku, Borecki, Ingrid B, Chasman, Daniel I, Pedersen, Oluf, Psaty, Bruce M, Tai, E. Shyong, van Duijn, Cornelia M, Wareham, Nicholas J, Waterworth, Dawn M, Boerwinkle, Eric, Kao, W. H. Linda, Florez, Jose C, Loos, Ruth J. F, Wilson, James G, Frayling, Timothy M, Siscovick, David S, Dupuis, Josée, Rotter, Jerome I, Meigs, James B, Scott, Robert A, Goodarzi, Mark O., Panico, Salvatore, Soranzo, Nicole [0000-0003-1095-3852], Johnson, Kathleen [0000-0002-6823-3252], Langenberg, Claudia [0000-0002-5017-7344], O'Rahilly, Stephen [0000-0003-2199-4449], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Epidemiology, Surgery, Internal Medicine, Radiology & Nuclear Medicine, Clinical Genetics, Obstetrics & Gynecology, and Cell biology
Subjects: Blood Glucose, diabetes, exome chip, SEQUENCING DATA, European Continental Ancestry Group, Black People, Genetic Association Studie, Endocrinology and Diabetes, TRIGLYCERIDE LEVELS, Polymorphism, Single Nucleotide, Article, White People, Glucagon-Like Peptide-1 Receptor, Cohort Studies, SDG 3 - Good Health and Well-being, Mutation Rate, GLYCEMIC TRAITS, Humans, Settore MED/14 - NEFROLOGIA, Insulin, Exome, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Genetic Association Studies, African Continental Ancestry Group, Oligonucleotide Array Sequence Analysis, PLASMA-GLUCOSE, INSULIN-RESISTANCE, epidemiology/genetics, Science & Technology, GLUCAGON-LIKE PEPTIDE-1, Diabetes, Genetic Variation, GERMLINE MUTATIONS, Fasting, epidemiology/genetics, Cohort Studies, Exome, diabetes, Multidisciplinary Sciences, RECEPTOR GENE, Diabetes Mellitus, Type 2, Genetic Loci, Endokrinologi och diabetes, CODING VARIATION, Glucose-6-Phosphatase, Science & Technology - Other Topics, exome chip, Human
Abstract: Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility., Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1R significantly associated with these traits.
Published: 2015

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources

Refine your results

128 results on '"Dawn M. Waterworth"'

101. We-P11:81 Association of insulin resistance with increased plasma transaminases levels in a Swiss population/the CoLaus study

102. Genetic Polymorphisms of the Main Transcription Factors for Adiponectin Gene Promoter in Regulation of Adiponectin Levels: Association Analysis in Three European Cohorts

103. Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals

104. A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol

105. Correction for Schumann et al., Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

106. Carriage of the V279F Null Allele within the Gene Encoding Lp-PLA2 Is Protective from Coronary Artery Disease in South Korean Males

107. Erratum: Corrigendum: Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

108. Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease

109. Meta-Analysis of 28,141 Individuals Identifies Common Variants within Five New Loci That Influence Uric Acid Concentrations

110. Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design?

111. Age-Related Effects of Genetic Variation on Lipid Levels: The Columbia University BioMarkers Study

112. The contribution of genetic variation to the postprandial response: Results from the european atherosclerosis research study (Earsii)

113. 1.P.278 Genetic variation in the apolipoprotein CIII gene and effects on plasma triglyceride levels in a large prospective study

114. 5' polymorphism of the CYP17 gene is not associated with serum testosterone levels in women with polycystic ovaries

115. Genetics and molecular biology

116. The Benefits of Using Genetic Information to Design Prevention Trials

117. The epigenetic signature of systemic insulin resistance in obese women

118. Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies

119. The Population Reference Sample, POPRES: A Resource for Population, Disease, and Pharmacological Genetics Research

120. Population-Based Genome-wide Association Studies Reveal Six Loci Influencing Plasma Levels of Liver Enzymes

121. Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

122. Identification and validation of copy number variants using SNP genotyping arrays from a large clinical cohort

123. Phenome-wide association study using research participants' self-reported data provides insight into the Th17 and IL-17 pathway.

124. Genome-wide association study of metabolic traits reveals novel gene-metabolite-disease links.

125. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

126. A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol.

127. Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.

128. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Catalog

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

128 results on '"Dawn M. Waterworth"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources