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 Baumert; Connie 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; Timothy Barnes; Suzanne Rafelt; Nienke Bruinsma; Lukas R. Dekker; José P. Henriques; Karel T. Koch; Robbert J. de Winter; Marco Alings; Cor F. Allaart; Anton P. Gorgels; Freek W. Verheugt; Nilesh J. Samani; 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; John Peden; 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; Muredach Reilly; 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; Peter Braund; 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

doi:10.1371/journal.pgen.1002260

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, Timothy Barnes, Suzanne Rafelt, Nienke Bruinsma, Lukas R. Dekker, José P. Henriques, Karel T. Koch, Robbert J. de Winter, Marco Alings, Cor F. Allaart, Anton P. Gorgels, Freek W. Verheugt, Nilesh J. Samani, 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, John Peden, 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, Muredach Reilly, 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, Peter Braund, 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

27 Citations (Scopus)

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 language	English
Article number	e1002260
Journal	PLoS Genetics
Volume	7
Issue number	9
ISSN	1553-7390
DOIs	https://doi.org/10.1371/journal.pgen.1002260
Publication status	Published - 01.09.2011

Research Areas and Centers

Research Area: Medical Genetics
Centers: Cardiological Center Luebeck (UHZL)

DFG Research Classification Scheme

205-12 Cardiology, Angiology
201-05 General Genetics and Functional Genomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1371/journal.pgen.1002260

Cite this

Butterworth, A. S., Braund, P. S., Farrall, M., Hardwick, R. J., Saleheen, D., Peden, J. F., Soranzo, N., Chambers, J. C., Sivapalaratnam, S., Kleber, M. E., Keating, B., Qasim, A., Klopp, N., Erdmann, J., Assimes, T. L., Ball, S. G., Balmforth, A. J., Barnes, T. A., Basart, H., ... Wallace, C. (2011). Large-scale gene-centric analysis identifies novel variants for coronary artery disease. PLoS Genetics, 7(9), Article e1002260. https://doi.org/10.1371/journal.pgen.1002260

@article{2a813c8d547440b390046a5469efe5c7,

title = "Large-scale gene-centric analysis identifies novel variants for coronary artery disease",

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.",

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

year = "2011",

month = sep,

day = "1",

doi = "10.1371/journal.pgen.1002260",

language = "English",

volume = "7",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "9",

}

Butterworth, AS, Braund, PS, Farrall, M, Hardwick, RJ, Saleheen, D, Peden, JF, Soranzo, N, Chambers, JC, Sivapalaratnam, S, Kleber, ME, Keating, B, Qasim, A, Klopp, N, Erdmann, J, Assimes, TL, Ball, SG, Balmforth, AJ, Barnes, TA, Basart, H, Baumert, J, Bezzina, CR, Boerwinkle, E, Boehm, BO, Brocheton, J, Bugert, P, Cambien, F, Clarke, R, Codd, V, Collins, R, Couper, D, Adrienne Cupples, L, de Jong, JS, Diemert, P, Ejebe, K, Elbers, CC, Elliott, P, Fornage, M, Franzosi, MG, Frossard, P, Garner, S, Goel, A, Goodall, AH, Hengstenberg, C, Hunt, SE, Kastelein, JJP, Klungel, OH, Klüterr, H, Koch, K, König, IR, Kooner, AS, Laaksonen, R, Lathrop, M, Li, M, Liu, K, McPherson, R, Musameh, MD, Musani, S, Nelson, CP, O'Donnell, CJ, Ongen, H, Papanicolaou, G, Peters, A, Peters, BJM, Potter, S, Psaty, BM, Qu, L, Rader, DJ, Rasheed, A, Rice, C, Scott, J, Seedorf, U, Sehmi, JS, Sotoodehnia, N, Stark, K, Stephens, J, van der Schoot, CE, van der Schouw, YT, Thorsteinsdottir, U, Tomaszewski, M, van der Harst, P, Vasan, RS, Wilde, AAM, Willenborg, C, Winkelmann, BR, Zaidi, M, Zhang, W, Ziegler, A, de Bakker, PIW, Koenig, W, März, W, Trip, MD, Reilly, MP, Kathiresan, S, Schunkert, H, Hamsten, A, Hall, AS, Kooner, JS, Thompson, SG, Thompson, JR, Deloukas, P, Ouwehand, WH, Watkins, H, Danesh, J, Samani, NJ, Barnes, T, Rafelt, S, Bruinsma, N, Dekker, LR, Henriques, JP, Koch, KT, de Winter, RJ, Alings, M, Allaart, CF, Gorgels, AP, Verheugt, FW, Samani, NJ, Mueller, M, Meisinger, C, DerOhannessian, S, Mehta, NN, Ferguson, J, Hakonarson, H, Matthai, W, Wilensky, R, Hopewell, JC, Parish, S, Linksted, P, Notman, J, Gonzalez, H, Young, A, Ostley, T, Munday, A, Goodwin, N, Verdon, V, Shah, S, Cobb, L, Edwards, C, Mathews, C, Gunter, R, Benham, J, Davies, C, Cobb, M, Crowther, J, Richards, A, Silver, M, Tochlin, S, Mozley, S, Clark, S, Radley, M, Kourellias, K, Olsson, P, Barlera, S, Tognoni, G, Rust, S, Assmann, G, Heath, S, Zelenika, D, Gut, I, Green, F, Peden, J, Aly, A, Anner, K, Björklund, K, Blomgren, G, Cederschiöld, B, Danell-Toverud, K, Eriksson, P, Grundstedt, U, Heinonen, M, Hellénius, ML, van't Hooft, F, Husman, K, Lagercrantz, J, Larsson, A, Larsson, M, Mossfeldt, M, Mälarstig, A, Olsson, G, Sabater-Lleal, M, Sennblad, B, Silveira, A, Strawbridge, R, Söderholm, B, Öhrvik, J, Shah Zaman, K, Hayat Mallick, N, Azhar, M, Samad, A, Ishaq, M, Shah, N, Samuel, M, Reilly, M, Holm, H, Preuss, M, Stewart, AFR, Barbalic, M, Gieger, C, Absher, D, Aherrahrou, Z, Allayee, H, Altshuler, D, Anand, S, Andersen, K, Anderson, JL, Ardissino, D, Becker, LC, Becker, DM, Berger, K, Bis, JC, Matthijs Boekholdt, S, Brown, MJ, Susan Burnett, M, Buysschaert, I, Carlquist, JF, Chen, L, Davies, RW, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, J, Do, R, Doering, A, El Mokhtari, NE, Ellis, SG, Elosua, R, Engert, JC, Epstein, S, de Faire, U, Fischer, M, Folsom, AR, Freyer, J, Gigante, B, Girelli, D, Gretarsdottir, S, Gudnason, V, Gulcher, JR, Tennstedt, S, Halperin, E, Hammond, N, Hazen, SL, Hofman, A, Horne, BD, Illig, T, Iribarren, C, Jones, GT, Wouter Jukema, J, Kaiser, MA, Kaplan, LM, Khaw, KT, Knowles, JW, Kolovou, G, Kong, A, Lambrechts, D, Leander, K, Lieb, W, Lettre, G, Loley, C, Lotery, AJ, Mannucci, PM, Maouche, S, Martinelli, N, McKeown, PP, Meitinger, T, Melander, O, Angelica Merlini, P, Mooser, V, Morgan, T, Mühleisen, TW, Muhlestein, JB, Musunuru, K, Nahrstaedt, J, Nöthen, MM, Olivieri, O, Peyvandi, F, Patel, RS, Patterson, CC, Quyyumi, AA, Rallidis, LS, Roosendaal, FR, Rubin, D, Salomaa, V, Lourdes Sampietro, M, Sandhu, MS, Schadt, E, Schäfer, A, Schillert, A, Schreiber, S, Schrezenmeir, J, Schwartz, SM, Siscovick, DS, Sivananthan, M, Smith, AV, Smith, TB, Snoep, JD, Spertus, JA, Stefansson, K, Stirrups, K, Stoll, M, Wilson Tang, WH, Thorgeirsson, G, Thorleifsson, G, Uitterlinden, AG, van Rij, AM, Voight, BF, Wareham, NJ, Wells, GA, Wichmann, HE, Witteman, JCM, Wright, BJ, Ye, S, Quertermous, T, Blankenberg, S, Roberts, R, Onland-Moret, NC, van Setten, J, Monique Verschuren, WM, Boer, JMA, Wijmenga, C, Hofker, MH, Maitland-van der Zee, AH, de Boer, A, Grobbee, DE, Attwood, T, Belz, S, Braund, P, Cooper, J, Crisp-Hihn, A, Foad, N, Gracey, J, Gray, E, Gwilliams, R, Heimerl, S, Jolley, J, Krishnan, U, Lloyd-Jones, H, Lugauer, I, Lundmark, P, Moore, JS, Muir, D, Murray, E, Neudert, J, Niblett, D, O'Leary, K, Pollard, H, Rankin, A, Rice, CM, Sager, H, Sambrook, J, Schmitz, G, Scholz, M, Schroeder, L, Syvannen, AC & Wallace, C 2011, 'Large-scale gene-centric analysis identifies novel variants for coronary artery disease', PLoS Genetics, vol. 7, no. 9, e1002260. https://doi.org/10.1371/journal.pgen.1002260

TY - JOUR

T1 - Large-scale gene-centric analysis identifies novel variants for coronary artery disease

AU - Butterworth, Adam S.

AU - Braund, Peter S.

AU - Farrall, Martin

AU - Hardwick, Robert J.

AU - Saleheen, Danish

AU - Peden, John F.

AU - Soranzo, Nicole

AU - Chambers, John C.

AU - Sivapalaratnam, Suthesh

AU - Kleber, Marcus E.

AU - Keating, Brendan

AU - Qasim, Atif

AU - Klopp, Norman

AU - Erdmann, Jeanette

AU - Assimes, Themistocles L.

AU - Ball, Stephen G.

AU - Balmforth, Anthony J.

AU - Barnes, Timothy A.

AU - Basart, Hanneke

AU - Baumert, Jens

AU - Bezzina, Connie R.

AU - Boerwinkle, Eric

AU - Boehm, Bernhard O.

AU - Brocheton, Jessy

AU - Bugert, Peter

AU - Cambien, Francois

AU - Clarke, Robert

AU - Codd, Veryan

AU - Collins, Rory

AU - Couper, David

AU - Adrienne Cupples, L.

AU - de Jong, Jonas S.

AU - Diemert, Patrick

AU - Ejebe, Kenechi

AU - Elbers, Clara C.

AU - Elliott, Paul

AU - Fornage, Myriam

AU - Franzosi, Maria Grazia

AU - Frossard, Philippe

AU - Garner, Stephen

AU - Goel, Anuj

AU - Goodall, Alison H.

AU - Hengstenberg, Christian

AU - Hunt, Sarah E.

AU - Kastelein, John J.P.

AU - Klungel, Olaf H.

AU - Klüterr, Harald

AU - Koch, Kerstin

AU - König, Inke R.

AU - Kooner, Angad S.

AU - Laaksonen, Reijo

AU - Lathrop, Mark

AU - Li, Mingyao

AU - Liu, Kiang

AU - McPherson, Ruth

AU - Musameh, Muntaser D.

AU - Musani, Solomon

AU - Nelson, Christopher P.

AU - O'Donnell, Christopher J.

AU - Ongen, Halit

AU - Papanicolaou, George

AU - Peters, Annette

AU - Peters, Bas J.M.

AU - Potter, Simon

AU - Psaty, Bruce M.

AU - Qu, Liming

AU - Rader, Daniel J.

AU - Rasheed, Asif

AU - Rice, Catherine

AU - Scott, James

AU - Seedorf, Udo

AU - Sehmi, Joban S.

AU - Sotoodehnia, Nona

AU - Stark, Klaus

AU - Stephens, Jonathan

AU - van der Schoot, C. Ellen

AU - van der Schouw, Yvonne T.

AU - Thorsteinsdottir, Unnur

AU - Tomaszewski, Maciej

AU - van der Harst, Pim

AU - Vasan, Ramachandran S.

AU - Wilde, Arthur A.M.

AU - Willenborg, Christina

AU - Winkelmann, Bernhard R.

AU - Zaidi, Moazzam

AU - Zhang, Weihua

AU - Ziegler, Andreas

AU - de Bakker, Paul I.W.

AU - Koenig, Wolfgang

AU - März, Winfried

AU - Trip, Mieke D.

AU - Reilly, Muredach P.

AU - Kathiresan, Sekar

AU - Schunkert, Heribert

AU - Hamsten, Anders

AU - Hall, Alistair S.

AU - Kooner, Jaspal S.

AU - Thompson, Simon G.

AU - Thompson, John R.

AU - Deloukas, Panos

AU - Ouwehand, Willem H.

AU - Watkins, Hugh

AU - Danesh, John

AU - Samani, Nilesh J.

AU - Barnes, Timothy

AU - Rafelt, Suzanne

AU - Bruinsma, Nienke

AU - Dekker, Lukas R.

AU - Henriques, José P.

AU - Koch, Karel T.

AU - de Winter, Robbert J.

AU - Alings, Marco

AU - Allaart, Cor F.

AU - Gorgels, Anton P.

AU - Verheugt, Freek W.

AU - Samani, Nilesh J.

AU - Mueller, Martina

AU - Meisinger, Christa

AU - DerOhannessian, Stephanie

AU - Mehta, Nehal N.

AU - Ferguson, Jane

AU - Hakonarson, Hakon

AU - Matthai, William

AU - Wilensky, Robert

AU - Hopewell, J. C.

AU - Parish, S.

AU - Linksted, P.

AU - Notman, J.

AU - Gonzalez, H.

AU - Young, A.

AU - Ostley, T.

AU - Munday, A.

AU - Goodwin, N.

AU - Verdon, V.

AU - Shah, S.

AU - Cobb, L.

AU - Edwards, C.

AU - Mathews, C.

AU - Gunter, R.

AU - Benham, J.

AU - Davies, C.

AU - Cobb, M.

AU - Crowther, J.

AU - Richards, A.

AU - Silver, M.

AU - Tochlin, S.

AU - Mozley, S.

AU - Clark, S.

AU - Radley, M.

AU - Kourellias, K.

AU - Olsson, Per

AU - Barlera, Simona

AU - Tognoni, Gianni

AU - Rust, Stephan

AU - Assmann, Gerd

AU - Heath, Simon

AU - Zelenika, Diana

AU - Gut, Ivo

AU - Green, Fiona

AU - Peden, John

AU - Aly, Anette

AU - Anner, Karolina

AU - Björklund, Karin

AU - Blomgren, Gun

AU - Cederschiöld, Barbro

AU - Danell-Toverud, Karin

AU - Eriksson, Per

AU - Grundstedt, Ulla

AU - Heinonen, Merja

AU - Hellénius, Mai Lis

AU - van't Hooft, Ferdinand

AU - Husman, Karin

AU - Lagercrantz, Jacob

AU - Larsson, Anita

AU - Larsson, Malin

AU - Mossfeldt, Magnus

AU - Mälarstig, Anders

AU - Olsson, Gunnar

AU - Sabater-Lleal, Maria

AU - Sennblad, Bengt

AU - Silveira, Angela

AU - Strawbridge, Rona

AU - Söderholm, Birgitta

AU - Öhrvik, John

AU - Shah Zaman, Khan

AU - Hayat Mallick, Nadeem

AU - Azhar, Muhammad

AU - Samad, Abdus

AU - Ishaq, Mohammad

AU - Shah, Nabi

AU - Samuel, Maria

AU - Reilly, Muredach

AU - Holm, Hilma

AU - Preuss, Michael

AU - Stewart, Alexandre F.R.

AU - Barbalic, Maja

AU - Gieger, Christian

AU - Absher, Devin

AU - Aherrahrou, Zouhair

AU - Allayee, Hooman

AU - Altshuler, David

AU - Anand, Sonia

AU - Andersen, Karl

AU - Anderson, Jeffrey L.

AU - Ardissino, Diego

AU - Becker, Lewis C.

AU - Becker, Diane M.

AU - Berger, Klaus

AU - Bis, Joshua C.

AU - Matthijs Boekholdt, S.

AU - Brown, Morris J.

AU - Susan Burnett, Mary

AU - Buysschaert, Ian

AU - Carlquist, John F.

AU - Chen, Li

AU - Davies, Robert W.

AU - Dedoussis, George

AU - Dehghan, Abbas

AU - Demissie, Serkalem

AU - Devaney, Joseph

AU - Do, Ron

AU - Doering, Angela

AU - El Mokhtari, Nour Eddine

AU - Ellis, Stephen G.

AU - Elosua, Roberto

AU - Engert, James C.

AU - Epstein, Stephen

AU - de Faire, Ulf

AU - Fischer, Marcus

AU - Folsom, Aaron R.

AU - Freyer, Jennifer

AU - Gigante, Bruna

AU - Girelli, Domenico

AU - Gretarsdottir, Solveig

AU - Gudnason, Vilmundur

AU - Gulcher, Jeffrey R.

AU - Tennstedt, Stephanie

AU - Halperin, Eran

AU - Hammond, Naomi

AU - Hazen, Stanley L.

AU - Hofman, Albert

AU - Horne, Benjamin D.

AU - Illig, Thomas

AU - Iribarren, Carlos

AU - Jones, Gregory T.

AU - Wouter Jukema, J.

AU - Kaiser, Michael A.

AU - Kaplan, Lee M.

AU - Khaw, Kay Tee

AU - Knowles, Joshua W.

AU - Kolovou, Genovefa

AU - Kong, Augustine

AU - Lambrechts, Diether

AU - Leander, Karin

AU - Lieb, Wolfgang

AU - Lettre, Guillaume

AU - Loley, Christina

AU - Lotery, Andrew J.

AU - Mannucci, Pier M.

AU - Maouche, Seraya

AU - Martinelli, Nicola

AU - McKeown, Pascal P.

AU - Meitinger, Thomas

AU - Melander, Olle

AU - Angelica Merlini, Pier

AU - Mooser, Vincent

AU - Morgan, Thomas

AU - Mühleisen, Thomas W.

AU - Muhlestein, Joseph B.

AU - Musunuru, Kiran

AU - Nahrstaedt, Janja

AU - Nöthen, Markus M.

AU - Olivieri, Oliviero

AU - Peyvandi, Flora

AU - Patel, Riyaz S.

AU - Patterson, Chris C.

AU - Quyyumi, Arshed A.

AU - Rallidis, Loukianos S.

AU - Roosendaal, Frits R.

AU - Rubin, Diana

AU - Salomaa, Veikko

AU - Lourdes Sampietro, M.

AU - Sandhu, Manj S.

AU - Schadt, Eric

AU - Schäfer, Arne

AU - Schillert, Arne

AU - Schreiber, Stefan

AU - Schrezenmeir, Jürgen

AU - Schwartz, Stephen M.

AU - Siscovick, David S.

AU - Sivananthan, Mohan

AU - Smith, Albert V.

AU - Smith, Tamara B.

AU - Snoep, Jaapjan D.

AU - Spertus, John A.

AU - Stefansson, Kari

AU - Stirrups, Kathy

AU - Stoll, Monika

AU - Wilson Tang, W. H.

AU - Thorgeirsson, Gudmundur

AU - Thorleifsson, Gudmar

AU - Uitterlinden, Andre G.

AU - van Rij, Andre M.

AU - Voight, Benjamin F.

AU - Wareham, Nick J.

AU - Wells, George A.

AU - Wichmann, H. Erich

AU - Witteman, Jaqueline C.M.

AU - Wright, Benjamin J.

AU - Ye, Shu

AU - Quertermous, Thomas

AU - Blankenberg, Stefan

AU - Roberts, Robert

AU - Onland-Moret, N. Charlotte

AU - van Setten, Jessica

AU - Monique Verschuren, W. M.

AU - Boer, Jolanda M.A.

AU - Wijmenga, Cisca

AU - Hofker, Marten H.

AU - Maitland-van der Zee, Anke Hilse

AU - de Boer, Anthonius

AU - Grobbee, Diederick E.

AU - Attwood, Tony

AU - Belz, Stephanie

AU - Braund, Peter

AU - Cooper, Jason

AU - Crisp-Hihn, Abi

AU - Foad, Nicola

AU - Gracey, Jay

AU - Gray, Emma

AU - Gwilliams, Rhian

AU - Heimerl, Susanne

AU - Jolley, Jennifer

AU - Krishnan, Unni

AU - Lloyd-Jones, Heather

AU - Lugauer, Ingrid

AU - Lundmark, Per

AU - Moore, Jasbir S.

AU - Muir, David

AU - Murray, Elizabeth

AU - Neudert, Jessica

AU - Niblett, David

AU - O'Leary, Karen

AU - Pollard, Helen

AU - Rankin, Angela

AU - Rice, Catherine M.

AU - Sager, Hendrik

AU - Sambrook, Jennifer

AU - Schmitz, Gerd

AU - Scholz, Michael

AU - Schroeder, Laura

AU - Syvannen, Ann Christine

AU - Wallace, Chris

PY - 2011/9/1

Y1 - 2011/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80053452394&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1002260

DO - 10.1371/journal.pgen.1002260

M3 - Journal articles

AN - SCOPUS:80053452394

SN - 1553-7390

VL - 7

JO - PLoS Genetics

JF - PLoS Genetics

IS - 9

M1 - e1002260

ER -

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

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