Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

Thomas R. Webb; Jeanette Erdmann; Kathleen E. Stirrups; Nathan O. Stitziel; Nicholas G.D. Masca; Henning Jansen; Stavroula Kanoni; Christopher P. Nelson; Paola G. Ferrario; Inke R. König; John D. Eicher; Andrew D. Johnson; Stephen E. Hamby; Christer Betsholtz; Arno Ruusalepp; Oscar Franzén; Eric E. Schadt; Johan L.M. Björkegren; Peter E. Weeke; Paul L. Auer; Ursula M. Schick; Yingchang Lu; He Zhang; Marie Pierre Dube; Anuj Goel; Martin Farrall; Gina M. Peloso; Hong Hee Won; Ron Do; Erik van Iperen; Jochen Kruppa; Anubha Mahajan; Robert A. Scott; Christina Willenborg; Peter S. Braund; Julian C. van Capelleveen; Alex S.F. Doney; Louise A. Donnelly; Rosanna Asselta; Pier A. Merlini; Stefano Duga; Nicola Marziliano; Josh C. Denny; Christian Shaffer; Nour Eddine El-Mokhtari; Andre Franke; Stefanie Heilmann; Christian Hengstenberg; Per Hoffmann; Oddgeir L. Holmen; Kristian Hveem; Jan Håkan Jansson; Karl Heinz Jöckel; Thorsten Kessler; Jennifer Kriebel; Karl L. Laugwitz; Eirini Marouli; Nicola Martinelli; Mark I. McCarthy; Natalie R. Van Zuydam; Christa Meisinger; Tõnu Esko; Evelin Mihailov; Stefan A. Escher; Maris Alver; Susanne Moebus; Andrew D. Morris; Jarma Virtamo; Majid Nikpay; Oliviero Olivieri; Sylvie Provost; Alaa AlQarawi; Neil R. Robertson; Karen O. Akinsansya; Dermot F. Reilly; Thomas F. Vogt; Wu Yin; Folkert W. Asselbergs; Charles Kooperberg; Rebecca D. Jackson; Eli Stahl; Martina Müller-Nurasyid; Konstantin Strauch; Tibor V. Varga; Melanie Waldenberger; Lingyao Zeng; Rajiv Chowdhury; Veikko Salomaa; Ian Ford; J. Wouter Jukema; Philippe Amouyel; Jukka Kontto; Børge G. Nordestgaard; Jean Ferrières; Danish Saleheen; Naveed Sattar; Praveen Surendran; Aline Wagner; Robin Young; Joanna M.M. Howson; Adam S. Butterworth; John Danesh; Diego Ardissino; Erwin P. Bottinger; Raimund Erbel; Paul W. Franks; Domenico Girelli; Alistair S. Hall; G. Kees Hovingh; Adnan Kastrati; Wolfgang Lieb; Thomas Meitinger; William E. Kraus; Svati H. Shah; Ruth McPherson; Marju Orho-Melander; Olle Melander; Andres Metspalu; Colin N.A. Palmer; Annette Peters; Daniel J. Rader; Muredach P. Reilly; Ruth J.F. Loos; Alex P. Reiner; Dan M. Roden; Jean Claude Tardif; John R. Thompson; Nicholas J. Wareham; Hugh Watkins; Cristen J. Willer; Nilesh J. Samani; Heribert Schunkert; Panos Deloukas; Sekar Kathiresan

doi:10.1016/j.jacc.2016.11.056

Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

Thomas R. Webb, Jeanette Erdmann, Kathleen E. Stirrups, Nathan O. Stitziel, Nicholas G.D. Masca, Henning Jansen, Stavroula Kanoni, Christopher P. Nelson, Paola G. Ferrario, Inke R. König, John D. Eicher, Andrew D. Johnson, Stephen E. Hamby, Christer Betsholtz, Arno Ruusalepp, Oscar Franzén, Eric E. Schadt, Johan L.M. Björkegren, Peter E. Weeke, Paul L. AuerUrsula M. Schick, Yingchang Lu, He Zhang, Marie Pierre Dube, Anuj Goel, Martin Farrall, Gina M. Peloso, Hong Hee Won, Ron Do, Erik van Iperen, Jochen Kruppa, Anubha Mahajan, Robert A. Scott, Christina Willenborg, Peter S. Braund, Julian C. van Capelleveen, Alex S.F. Doney, Louise A. Donnelly, Rosanna Asselta, Pier A. Merlini, Stefano Duga, Nicola Marziliano, Josh C. Denny, Christian Shaffer, Nour Eddine El-Mokhtari, Andre Franke, Stefanie Heilmann, Christian Hengstenberg, Per Hoffmann, Oddgeir L. Holmen, Kristian Hveem, Jan Håkan Jansson, Karl Heinz Jöckel, Thorsten Kessler, Jennifer Kriebel, Karl L. Laugwitz, Eirini Marouli, Nicola Martinelli, Mark I. McCarthy, Natalie R. Van Zuydam, Christa Meisinger, Tõnu Esko, Evelin Mihailov, Stefan A. Escher, Maris Alver, Susanne Moebus, Andrew D. Morris, Jarma Virtamo, Majid Nikpay, Oliviero Olivieri, Sylvie Provost, Alaa AlQarawi, Neil R. Robertson, Karen O. Akinsansya, Dermot F. Reilly, Thomas F. Vogt, Wu Yin, Folkert W. Asselbergs, Charles Kooperberg, Rebecca D. Jackson, Eli Stahl, Martina Müller-Nurasyid, Konstantin Strauch, Tibor V. Varga, Melanie Waldenberger, Lingyao Zeng, Rajiv Chowdhury, Veikko Salomaa, Ian Ford, J. Wouter Jukema, Philippe Amouyel, Jukka Kontto, Børge G. Nordestgaard, Jean Ferrières, Danish Saleheen, Naveed Sattar, Praveen Surendran, Aline Wagner, Robin Young, Joanna M.M. Howson, Adam S. Butterworth, John Danesh, Diego Ardissino, Erwin P. Bottinger, Raimund Erbel, Paul W. Franks, Domenico Girelli, Alistair S. Hall, G. Kees Hovingh, Adnan Kastrati, Wolfgang Lieb, Thomas Meitinger, William E. Kraus, Svati H. Shah, Ruth McPherson, Marju Orho-Melander, Olle Melander, Andres Metspalu, Colin N.A. Palmer, Annette Peters, Daniel J. Rader, Muredach P. Reilly, Ruth J.F. Loos, Alex P. Reiner, Dan M. Roden, Jean Claude Tardif, John R. Thompson, Nicholas J. Wareham, Hugh Watkins, Cristen J. Willer, Nilesh J. Samani, Heribert Schunkert, Panos Deloukas, Sekar Kathiresan

Research output: Contribution to journal › Article › peer-review

195 Scopus citations

Abstract

Background Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. Objectives This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. Methods In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. Results We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10⁻⁴ with a range of other diseases/traits. Conclusions We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.

Original language	English
Pages (from-to)	823-836
Number of pages	14
Journal	Journal of the American College of Cardiology
Volume	69
Issue number	7
DOIs	https://doi.org/10.1016/j.jacc.2016.11.056
State	Published - 21 Feb 2017

Keywords

cholesteryl ester transfer protein
expression quantitative trait loci
genetics
genome-wide association
single nucleotide polymorphism

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10.1016/j.jacc.2016.11.056

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Webb, T. R., Erdmann, J., Stirrups, K. E., Stitziel, N. O., Masca, N. G. D., Jansen, H., Kanoni, S., Nelson, C. P., Ferrario, P. G., König, I. R., Eicher, J. D., Johnson, A. D., Hamby, S. E., Betsholtz, C., Ruusalepp, A., Franzén, O., Schadt, E. E., Björkegren, J. L. M., Weeke, P. E., ... Kathiresan, S. (2017). Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease. Journal of the American College of Cardiology, 69(7), 823-836. https://doi.org/10.1016/j.jacc.2016.11.056

@article{79b815b4027842679fe412bb68bf2fa9,

title = "Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease",

abstract = "Background Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. Objectives This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. Methods In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. Results We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10−4 with a range of other diseases/traits. Conclusions We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.",

keywords = "cholesteryl ester transfer protein, expression quantitative trait loci, genetics, genome-wide association, single nucleotide polymorphism",

author = "Webb, {Thomas R.} and Jeanette Erdmann and Stirrups, {Kathleen E.} and Stitziel, {Nathan O.} and Masca, {Nicholas G.D.} and Henning Jansen and Stavroula Kanoni and Nelson, {Christopher P.} and Ferrario, {Paola G.} and K{\"o}nig, {Inke R.} and Eicher, {John D.} and Johnson, {Andrew D.} and Hamby, {Stephen E.} and Christer Betsholtz and Arno Ruusalepp and Oscar Franz{\'e}n and Schadt, {Eric E.} and Bj{\"o}rkegren, {Johan L.M.} and Weeke, {Peter E.} and Auer, {Paul L.} and Schick, {Ursula M.} and Yingchang Lu and He Zhang and Dube, {Marie Pierre} and Anuj Goel and Martin Farrall and Peloso, {Gina M.} and Won, {Hong Hee} and Ron Do and {van Iperen}, Erik and Jochen Kruppa and Anubha Mahajan and Scott, {Robert A.} and Christina Willenborg and Braund, {Peter S.} and {van Capelleveen}, {Julian C.} and Doney, {Alex S.F.} and Donnelly, {Louise A.} and Rosanna Asselta and Merlini, {Pier A.} and Stefano Duga and Nicola Marziliano and Denny, {Josh C.} and Christian Shaffer and El-Mokhtari, {Nour Eddine} and Andre Franke and Stefanie Heilmann and Christian Hengstenberg and Per Hoffmann and Holmen, {Oddgeir L.} and Kristian Hveem and Jansson, {Jan H{\aa}kan} and J{\"o}ckel, {Karl Heinz} and Thorsten Kessler and Jennifer Kriebel and Laugwitz, {Karl L.} and Eirini Marouli and Nicola Martinelli and McCarthy, {Mark I.} and {Van Zuydam}, {Natalie R.} and Christa Meisinger and T{\~o}nu Esko and Evelin Mihailov and Escher, {Stefan A.} and Maris Alver and Susanne Moebus and Morris, {Andrew D.} and Jarma Virtamo and Majid Nikpay and Oliviero Olivieri and Sylvie Provost and Alaa AlQarawi and Robertson, {Neil R.} and Akinsansya, {Karen O.} and Reilly, {Dermot F.} and Vogt, {Thomas F.} and Wu Yin and Asselbergs, {Folkert W.} and Charles Kooperberg and Jackson, {Rebecca D.} and Eli Stahl and Martina M{\"u}ller-Nurasyid and Konstantin Strauch and Varga, {Tibor V.} and Melanie Waldenberger and Lingyao Zeng and Rajiv Chowdhury and Veikko Salomaa and Ian Ford and Jukema, {J. Wouter} and Philippe Amouyel and Jukka Kontto and Nordestgaard, {B{\o}rge G.} and Jean Ferri{\`e}res and Danish Saleheen and Naveed Sattar and Praveen Surendran and Aline Wagner and Robin Young and Howson, {Joanna M.M.} and Butterworth, {Adam S.} and John Danesh and Diego Ardissino and Bottinger, {Erwin P.} and Raimund Erbel and Franks, {Paul W.} and Domenico Girelli and Hall, {Alistair S.} and Hovingh, {G. Kees} and Adnan Kastrati and Wolfgang Lieb and Thomas Meitinger and Kraus, {William E.} and Shah, {Svati H.} and Ruth McPherson and Marju Orho-Melander and Olle Melander and Andres Metspalu and Palmer, {Colin N.A.} and Annette Peters and Rader, {Daniel J.} and Reilly, {Muredach P.} and Loos, {Ruth J.F.} and Reiner, {Alex P.} and Roden, {Dan M.} and Tardif, {Jean Claude} and Thompson, {John R.} and Wareham, {Nicholas J.} and Hugh Watkins and Willer, {Cristen J.} and Samani, {Nilesh J.} and Heribert Schunkert and Panos Deloukas and Sekar Kathiresan",

note = "Publisher Copyright: {\textcopyright} 2017 The Authors",

year = "2017",

month = feb,

day = "21",

doi = "10.1016/j.jacc.2016.11.056",

language = "English",

volume = "69",

pages = "823--836",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier USA",

number = "7",

}

Webb, TR, Erdmann, J, Stirrups, KE, Stitziel, NO, Masca, NGD, Jansen, H, Kanoni, S, Nelson, CP, Ferrario, PG, König, IR, Eicher, JD, Johnson, AD, Hamby, SE, Betsholtz, C, Ruusalepp, A, Franzén, O, Schadt, EE, Björkegren, JLM, Weeke, PE, Auer, PL, Schick, UM, Lu, Y, Zhang, H, Dube, MP, Goel, A, Farrall, M, Peloso, GM, Won, HH, Do, R, van Iperen, E, Kruppa, J, Mahajan, A, Scott, RA, Willenborg, C, Braund, PS, van Capelleveen, JC, Doney, ASF, Donnelly, LA, Asselta, R, Merlini, PA, Duga, S, Marziliano, N, Denny, JC, Shaffer, C, El-Mokhtari, NE, Franke, A, Heilmann, S, Hengstenberg, C, Hoffmann, P, Holmen, OL, Hveem, K, Jansson, JH, Jöckel, KH, Kessler, T, Kriebel, J, Laugwitz, KL, Marouli, E, Martinelli, N, McCarthy, MI, Van Zuydam, NR, Meisinger, C, Esko, T, Mihailov, E, Escher, SA, Alver, M, Moebus, S, Morris, AD, Virtamo, J, Nikpay, M, Olivieri, O, Provost, S, AlQarawi, A, Robertson, NR, Akinsansya, KO, Reilly, DF, Vogt, TF, Yin, W, Asselbergs, FW, Kooperberg, C, Jackson, RD, Stahl, E, Müller-Nurasyid, M, Strauch, K, Varga, TV, Waldenberger, M, Zeng, L, Chowdhury, R, Salomaa, V, Ford, I, Jukema, JW, Amouyel, P, Kontto, J, Nordestgaard, BG, Ferrières, J, Saleheen, D, Sattar, N, Surendran, P, Wagner, A, Young, R, Howson, JMM, Butterworth, AS, Danesh, J, Ardissino, D, Bottinger, EP, Erbel, R, Franks, PW, Girelli, D, Hall, AS, Hovingh, GK, Kastrati, A, Lieb, W, Meitinger, T, Kraus, WE, Shah, SH, McPherson, R, Orho-Melander, M, Melander, O, Metspalu, A, Palmer, CNA, Peters, A, Rader, DJ, Reilly, MP, Loos, RJF, Reiner, AP, Roden, DM, Tardif, JC, Thompson, JR, Wareham, NJ, Watkins, H, Willer, CJ, Samani, NJ, Schunkert, H, Deloukas, P & Kathiresan, S 2017, 'Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease', Journal of the American College of Cardiology, vol. 69, no. 7, pp. 823-836. https://doi.org/10.1016/j.jacc.2016.11.056

TY - JOUR

T1 - Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

AU - Webb, Thomas R.

AU - Erdmann, Jeanette

AU - Stirrups, Kathleen E.

AU - Stitziel, Nathan O.

AU - Masca, Nicholas G.D.

AU - Jansen, Henning

AU - Kanoni, Stavroula

AU - Nelson, Christopher P.

AU - Ferrario, Paola G.

AU - König, Inke R.

AU - Eicher, John D.

AU - Johnson, Andrew D.

AU - Hamby, Stephen E.

AU - Betsholtz, Christer

AU - Ruusalepp, Arno

AU - Franzén, Oscar

AU - Schadt, Eric E.

AU - Björkegren, Johan L.M.

AU - Weeke, Peter E.

AU - Auer, Paul L.

AU - Schick, Ursula M.

AU - Lu, Yingchang

AU - Zhang, He

AU - Dube, Marie Pierre

AU - Goel, Anuj

AU - Farrall, Martin

AU - Peloso, Gina M.

AU - Won, Hong Hee

AU - Do, Ron

AU - van Iperen, Erik

AU - Kruppa, Jochen

AU - Mahajan, Anubha

AU - Scott, Robert A.

AU - Willenborg, Christina

AU - Braund, Peter S.

AU - van Capelleveen, Julian C.

AU - Doney, Alex S.F.

AU - Donnelly, Louise A.

AU - Asselta, Rosanna

AU - Merlini, Pier A.

AU - Duga, Stefano

AU - Marziliano, Nicola

AU - Denny, Josh C.

AU - Shaffer, Christian

AU - El-Mokhtari, Nour Eddine

AU - Franke, Andre

AU - Heilmann, Stefanie

AU - Hengstenberg, Christian

AU - Hoffmann, Per

AU - Holmen, Oddgeir L.

AU - Hveem, Kristian

AU - Jansson, Jan Håkan

AU - Jöckel, Karl Heinz

AU - Kessler, Thorsten

AU - Kriebel, Jennifer

AU - Laugwitz, Karl L.

AU - Marouli, Eirini

AU - Martinelli, Nicola

AU - McCarthy, Mark I.

AU - Van Zuydam, Natalie R.

AU - Meisinger, Christa

AU - Esko, Tõnu

AU - Mihailov, Evelin

AU - Escher, Stefan A.

AU - Alver, Maris

AU - Moebus, Susanne

AU - Morris, Andrew D.

AU - Virtamo, Jarma

AU - Nikpay, Majid

AU - Olivieri, Oliviero

AU - Provost, Sylvie

AU - AlQarawi, Alaa

AU - Robertson, Neil R.

AU - Akinsansya, Karen O.

AU - Reilly, Dermot F.

AU - Vogt, Thomas F.

AU - Yin, Wu

AU - Asselbergs, Folkert W.

AU - Kooperberg, Charles

AU - Jackson, Rebecca D.

AU - Stahl, Eli

AU - Müller-Nurasyid, Martina

AU - Strauch, Konstantin

AU - Varga, Tibor V.

AU - Waldenberger, Melanie

AU - Zeng, Lingyao

AU - Chowdhury, Rajiv

AU - Salomaa, Veikko

AU - Ford, Ian

AU - Jukema, J. Wouter

AU - Amouyel, Philippe

AU - Kontto, Jukka

AU - Nordestgaard, Børge G.

AU - Ferrières, Jean

AU - Saleheen, Danish

AU - Sattar, Naveed

AU - Surendran, Praveen

AU - Wagner, Aline

AU - Young, Robin

AU - Howson, Joanna M.M.

AU - Butterworth, Adam S.

AU - Danesh, John

AU - Ardissino, Diego

AU - Bottinger, Erwin P.

AU - Erbel, Raimund

AU - Franks, Paul W.

AU - Girelli, Domenico

AU - Hall, Alistair S.

AU - Hovingh, G. Kees

AU - Kastrati, Adnan

AU - Lieb, Wolfgang

AU - Meitinger, Thomas

AU - Kraus, William E.

AU - Shah, Svati H.

AU - McPherson, Ruth

AU - Orho-Melander, Marju

AU - Melander, Olle

AU - Metspalu, Andres

AU - Palmer, Colin N.A.

AU - Peters, Annette

AU - Rader, Daniel J.

AU - Reilly, Muredach P.

AU - Loos, Ruth J.F.

AU - Reiner, Alex P.

AU - Roden, Dan M.

AU - Tardif, Jean Claude

AU - Thompson, John R.

AU - Wareham, Nicholas J.

AU - Watkins, Hugh

AU - Willer, Cristen J.

AU - Samani, Nilesh J.

AU - Schunkert, Heribert

AU - Deloukas, Panos

AU - Kathiresan, Sekar

PY - 2017/2/21

Y1 - 2017/2/21

N2 - Background Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. Objectives This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. Methods In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. Results We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10−4 with a range of other diseases/traits. Conclusions We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.

AB - Background Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. Objectives This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. Methods In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. Results We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10−4 with a range of other diseases/traits. Conclusions We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.

KW - cholesteryl ester transfer protein

KW - expression quantitative trait loci

KW - genetics

KW - genome-wide association

KW - single nucleotide polymorphism

UR - http://www.scopus.com/inward/record.url?scp=85013005062&partnerID=8YFLogxK

U2 - 10.1016/j.jacc.2016.11.056

DO - 10.1016/j.jacc.2016.11.056

M3 - Article

C2 - 28209224

AN - SCOPUS:85013005062

SN - 0735-1097

VL - 69

SP - 823

EP - 836

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 7

ER -

Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

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