Large-scale gene-centric analysis identifies novel variants for coronary artery disease

Adam S. Butterworth, Peter S. Braund, Martin Farrall, Robert J. Hardwick, Danish Saleheen, John F. Peden, Nicole Soranzo, John C. Chambers, Suthesh Sivapalaratnam, Marcus E. Kleber, Brendan Keating, Atif Qasim, Norman Klopp, Jeanette Erdmann, Themistocles L. Assimes, Stephen G. Ball, Anthony J. Balmforth, Timothy A. Barnes, Hanneke Basart, Jens BaumertConnie R. Bezzina, Eric Boerwinkle, Bernhard O. Boehm, Jessy Brocheton, Peter Bugert, Francois Cambien, Robert Clarke, Veryan Codd, Rory Collins, David Couper, L. Adrienne Cupples, Jonas S. de Jong, Patrick Diemert, Kenechi Ejebe, Clara C. Elbers, Paul Elliott, Myriam Fornage, Maria Grazia Franzosi, Philippe Frossard, Stephen Garner, Anuj Goel, Alison H. Goodall, Christian Hengstenberg, Sarah E. Hunt, John J.P. Kastelein, Olaf H. Klungel, Harald Klüterr, Kerstin Koch, Inke R. König, Angad S. Kooner, Reijo Laaksonen, Mark Lathrop, Mingyao Li, Kiang Liu, Ruth McPherson, Muntaser D. Musameh, Solomon Musani, Christopher P. Nelson, Christopher J. O'Donnell, Halit Ongen, George Papanicolaou, Annette Peters, Bas J.M. Peters, Simon Potter, Bruce M. Psaty, Liming Qu, Daniel J. Rader, Asif Rasheed, Catherine Rice, James Scott, Udo Seedorf, Joban S. Sehmi, Nona Sotoodehnia, Klaus Stark, Jonathan Stephens, C. Ellen van der Schoot, Yvonne T. van der Schouw, Unnur Thorsteinsdottir, Maciej Tomaszewski, Pim van der Harst, Ramachandran S. Vasan, Arthur A.M. Wilde, Christina Willenborg, Bernhard R. Winkelmann, Moazzam Zaidi, Weihua Zhang, Andreas Ziegler, Paul I.W. de Bakker, Wolfgang Koenig, Winfried März, Mieke D. Trip, Muredach P. Reilly, Sekar Kathiresan, Heribert Schunkert, Anders Hamsten, Alistair S. Hall, Jaspal S. Kooner, Simon G. Thompson, John R. Thompson, Panos Deloukas, Willem H. Ouwehand, Hugh Watkins, John Danesh, Nilesh J. Samani, Suzanne Rafelt, Nienke Bruinsma, Lukas R. Dekker, José P. Henriques, Robbert J. de Winter, Marco Alings, Cor F. Allaart, Anton P. Gorgels, Freek W. Verheugt, Martina Mueller, Christa Meisinger, Stephanie DerOhannessian, Nehal N. Mehta, Jane Ferguson, Hakon Hakonarson, William Matthai, Robert Wilensky, J. C. Hopewell, S. Parish, P. Linksted, J. Notman, H. Gonzalez, A. Young, T. Ostley, A. Munday, N. Goodwin, V. Verdon, S. Shah, L. Cobb, C. Edwards, C. Mathews, R. Gunter, J. Benham, C. Davies, M. Cobb, J. Crowther, A. Richards, M. Silver, S. Tochlin, S. Mozley, S. Clark, M. Radley, K. Kourellias, Per Olsson, Simona Barlera, Gianni Tognoni, Stephan Rust, Gerd Assmann, Simon Heath, Diana Zelenika, Ivo Gut, Fiona Green, Anette Aly, Karolina Anner, Karin Björklund, Gun Blomgren, Barbro Cederschiöld, Karin Danell-Toverud, Per Eriksson, Ulla Grundstedt, Merja Heinonen, Mai Lis Hellénius, Ferdinand van't Hooft, Karin Husman, Jacob Lagercrantz, Anita Larsson, Malin Larsson, Magnus Mossfeldt, Anders Mälarstig, Gunnar Olsson, Maria Sabater-Lleal, Bengt Sennblad, Angela Silveira, Rona Strawbridge, Birgitta Söderholm, John Öhrvik, Khan Shah Zaman, Nadeem Hayat Mallick, Muhammad Azhar, Abdus Samad, Mohammad Ishaq, Nabi Shah, Maria Samuel, Hilma Holm, Michael Preuss, Alexandre F.R. Stewart, Maja Barbalic, Christian Gieger, Devin Absher, Zouhair Aherrahrou, Hooman Allayee, David Altshuler, Sonia Anand, Karl Andersen, Jeffrey L. Anderson, Diego Ardissino, Lewis C. Becker, Diane M. Becker, Klaus Berger, Joshua C. Bis, S. Matthijs Boekholdt, Morris J. Brown, Mary Susan Burnett, Ian Buysschaert, John F. Carlquist, Li Chen, Robert W. Davies, George Dedoussis, Abbas Dehghan, Serkalem Demissie, Joseph Devaney, Ron Do, Angela Doering, Nour Eddine El Mokhtari, Stephen G. Ellis, Roberto Elosua, James C. Engert, Stephen Epstein, Ulf de Faire, Marcus Fischer, Aaron R. Folsom, Jennifer Freyer, Bruna Gigante, Domenico Girelli, Solveig Gretarsdottir, Vilmundur Gudnason, Jeffrey R. Gulcher, Stephanie Tennstedt, Eran Halperin, Naomi Hammond, Stanley L. Hazen, Albert Hofman, Benjamin D. Horne, Thomas Illig, Carlos Iribarren, Gregory T. Jones, J. Wouter Jukema, Michael A. Kaiser, Lee M. Kaplan, Kay Tee Khaw, Joshua W. Knowles, Genovefa Kolovou, Augustine Kong, Diether Lambrechts, Karin Leander, Wolfgang Lieb, Guillaume Lettre, Christina Loley, Andrew J. Lotery, Pier M. Mannucci, Seraya Maouche, Nicola Martinelli, Pascal P. McKeown, Thomas Meitinger, Olle Melander, Pier Angelica Merlini, Vincent Mooser, Thomas Morgan, Thomas W. Mühleisen, Joseph B. Muhlestein, Kiran Musunuru, Janja Nahrstaedt, Markus M. Nöthen, Oliviero Olivieri, Flora Peyvandi, Riyaz S. Patel, Chris C. Patterson, Arshed A. Quyyumi, Loukianos S. Rallidis, Frits R. Roosendaal, Diana Rubin, Veikko Salomaa, M. Lourdes Sampietro, Manj S. Sandhu, Eric Schadt, Arne Schäfer, Arne Schillert, Stefan Schreiber, Jürgen Schrezenmeir, Stephen M. Schwartz, David S. Siscovick, Mohan Sivananthan, Albert V. Smith, Tamara B. Smith, Jaapjan D. Snoep, John A. Spertus, Kari Stefansson, Kathy Stirrups, Monika Stoll, W. H. Wilson Tang, Gudmundur Thorgeirsson, Gudmar Thorleifsson, Andre G. Uitterlinden, Andre M. van Rij, Benjamin F. Voight, Nick J. Wareham, George A. Wells, H. Erich Wichmann, Jaqueline C.M. Witteman, Benjamin J. Wright, Shu Ye, Thomas Quertermous, Stefan Blankenberg, Robert Roberts, N. Charlotte Onland-Moret, Jessica van Setten, W. M. Monique Verschuren, Jolanda M.A. Boer, Cisca Wijmenga, Marten H. Hofker, Anke Hilse Maitland-van der Zee, Anthonius de Boer, Diederick E. Grobbee, Tony Attwood, Stephanie Belz, Jason Cooper, Abi Crisp-Hihn, Nicola Foad, Jay Gracey, Emma Gray, Rhian Gwilliams, Susanne Heimerl, Jennifer Jolley, Unni Krishnan, Heather Lloyd-Jones, Ingrid Lugauer, Per Lundmark, Jasbir S. Moore, David Muir, Elizabeth Murray, Jessica Neudert, David Niblett, Karen O'Leary, Helen Pollard, Angela Rankin, Catherine M. Rice, Hendrik Sager, Jennifer Sambrook, Gerd Schmitz, Michael Scholz, Laura Schroeder, Ann Christine Syvannen, Chris Wallace

Research output: Contribution to journalArticlepeer-review

Abstract

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ~2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10-33; LPA:p<10-19; 1p13.3:p<10-17) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10-7). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ~4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.

Original languageEnglish (US)
Article numbere1002260
JournalPLoS genetics
Volume7
Issue number9
DOIs
StatePublished - Sep 1 2011

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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