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; Andrew D Morris; Colin N A Palmer; Wellcome Trust Case Control Consortium, MORGAM Investigators, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators; Nilesh J. Samani; Panos Deloukas

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, Andrew D Morris, Colin N A Palmer, Wellcome Trust Case Control Consortium, MORGAM Investigators, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators, Nilesh J. Samani (Lead / Corresponding author), Panos Deloukas (Lead / Corresponding author)

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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
Early online date	13 Feb 2017
DOIs	https://doi.org/10.1016/j.jacc.2016.11.056
Publication status	Published - 21 Feb 2017

Keywords

Cholesteryl ester transfer protein
Expression quantitative trait loci
Genetics
Genome-wide association
Single nucleotide polymorphism

UN SDGs

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

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© 2017 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY LICENSE (http://creativecommons.org/licenses/by/4.0/)
Final published version, 549 KBLicence: CC BY

The Scottish eHealth Informatics Research Centre (E-HIRCs) (Joint with Universities of Aberdeen, Glasgow, Edinburgh, Strathclyde, St Andrews & Leicester and ISD)
Colhoun, H. (Investigator), Donnan, P. (Investigator), Guthrie, B. (Investigator), Jefferson, E. (Investigator), MacDonald, T. (Investigator), McCowan, C. (Investigator), Morris, A. (Investigator), Pearson, E. (Investigator), Sullivan, F. (Investigator) & Swedlow, J. (Investigator)
Medical Research Council
1/03/13 → 31/12/18
Project: Research

Doney, Alexander
- Cardiovascular Research - Clinical Reader (Teaching and Research)
Person: Academic
Palmer, Colin
- Population Health and Genomics - Professor (Teaching and Research) of Pharmacogenomics
Person: Academic

Cite this

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., ... Deloukas, P. (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{5275b6c3ab6e4ecb953e719ff5b5f31e,

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 Marie-Pierre Dube and Anuj Goel and Martin Farrall and Peloso, {Gina M} and Hong-Hee Won 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 Morris, {Andrew D} and Palmer, {Colin N A} and {Wellcome Trust Case Control Consortium, MORGAM Investigators, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators} and Samani, {Nilesh J.} and Panos Deloukas",

note = "A FULL LIST OF ACKNOWLEDGEMENTS AND FUNDING SOURCES IS INCLUDED IN THE ONLINE APPENDIX Drs. Akinsanya, Wu, Yin, and Reilly are employees of Merck Sharp & Dohme; and Dr. Vogt was an employee of Merck when aspects of this research was conducted, but is now retired from Merck. A cholesteryl ester transfer protein inhibitor, Anacetrapib (MK-0859), is currently undergoing clinical investigation in the REVEAL outcome trial sponsored by Merck Sharp & Dohme. Dr. Schick is an employee of Recombine. Dr. Dube has equity in DalCor Pharmaceuticals. Dr. McCarthy is a member of advisory boards for Pfizer and Novo Nordisk; has received honoraria from Pfizer, Novo Nordisk, and Eli Lilly; and has received research funding provided by Pfizer, Novo Nordisk, Eli Lilly, Servier, Sanofi-Aventis, Janssen, Roche, Boehringer-Ingelheim, Takeda, Merck, and AstraZeneca. Dr. Ferrieres has received grants from Merck Sharp & Dohme, Amgen, and Sanofi. Dr. Sattar has served as a consultant for Amgen and Sanofi. Dr. Butterworth has received grants from Pfizer and Merck. Dr. Danesh has served as a consultant for Takeda; has served on the Novartis Cardiovascular & Metabolic Advisory Board and International Cardiovascular and Metabolism Research and Development Portfolio Committee of Novartis; has served on the UK Atherosclerosis Advisory Board of Merck Sharp & Dohme; has served on the advisory board of Sanofi; has served on the Pfizer Population Research Advisory Panel; and has financial relationships with the British Heart Foundation, BUPA Foundation, diaDexus, European Research Council, European Union, Evelyn Trust, Fogarty International Centre, GlaxoSmithKline, Merck, National Heart, Lung, and Blood Institute, National Health Service Blood and Transplant, National Institute for Health Research, National Institute of Neurological Disorders and Stroke, Novartis, Pfizer, Roche, Sanofi, Takeda, The Wellcome Trust, UK Biobank, University of British Columbia, and UK Medical Research Council. Dr. Tardif has received research grants from Amarin, AstraZeneca, Merck, Pfizer, Eli Lilly, Sanofi, Servier, and DalCor; has received honoraria from Pfizer (to his institution), Servier, DalCor, and Sanofi (to his institution); and has received modest equity interest from DalCor. Dr. Kathiresan has financial/other relationships with Regeneron, Bayer, Catabasis, Merck, Celera, Genomics PLC, San Therapeutics, Novartis, Sanofi, AstraZeneca, Alnylam, Eli Lilly, Leerink Partners, and Noble Insights. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. ",

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",

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, M-P, Goel, A, Farrall, M, Peloso, GM, Won, H-H, 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, Morris, AD, Palmer, CNA, Wellcome Trust Case Control Consortium, MORGAM Investigators, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators, Samani, NJ & Deloukas, P 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 - Morris, Andrew D

AU - Palmer, Colin N A

AU - Wellcome Trust Case Control Consortium, MORGAM Investigators, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators

AU - Samani, Nilesh J.

AU - Deloukas, Panos

N1 - A FULL LIST OF ACKNOWLEDGEMENTS AND FUNDING SOURCES IS INCLUDED IN THE ONLINE APPENDIX Drs. Akinsanya, Wu, Yin, and Reilly are employees of Merck Sharp & Dohme; and Dr. Vogt was an employee of Merck when aspects of this research was conducted, but is now retired from Merck. A cholesteryl ester transfer protein inhibitor, Anacetrapib (MK-0859), is currently undergoing clinical investigation in the REVEAL outcome trial sponsored by Merck Sharp & Dohme. Dr. Schick is an employee of Recombine. Dr. Dube has equity in DalCor Pharmaceuticals. Dr. McCarthy is a member of advisory boards for Pfizer and Novo Nordisk; has received honoraria from Pfizer, Novo Nordisk, and Eli Lilly; and has received research funding provided by Pfizer, Novo Nordisk, Eli Lilly, Servier, Sanofi-Aventis, Janssen, Roche, Boehringer-Ingelheim, Takeda, Merck, and AstraZeneca. Dr. Ferrieres has received grants from Merck Sharp & Dohme, Amgen, and Sanofi. Dr. Sattar has served as a consultant for Amgen and Sanofi. Dr. Butterworth has received grants from Pfizer and Merck. Dr. Danesh has served as a consultant for Takeda; has served on the Novartis Cardiovascular & Metabolic Advisory Board and International Cardiovascular and Metabolism Research and Development Portfolio Committee of Novartis; has served on the UK Atherosclerosis Advisory Board of Merck Sharp & Dohme; has served on the advisory board of Sanofi; has served on the Pfizer Population Research Advisory Panel; and has financial relationships with the British Heart Foundation, BUPA Foundation, diaDexus, European Research Council, European Union, Evelyn Trust, Fogarty International Centre, GlaxoSmithKline, Merck, National Heart, Lung, and Blood Institute, National Health Service Blood and Transplant, National Institute for Health Research, National Institute of Neurological Disorders and Stroke, Novartis, Pfizer, Roche, Sanofi, Takeda, The Wellcome Trust, UK Biobank, University of British Columbia, and UK Medical Research Council. Dr. Tardif has received research grants from Amarin, AstraZeneca, Merck, Pfizer, Eli Lilly, Sanofi, Servier, and DalCor; has received honoraria from Pfizer (to his institution), Servier, DalCor, and Sanofi (to his institution); and has received modest equity interest from DalCor. Dr. Kathiresan has financial/other relationships with Regeneron, Bayer, Catabasis, Merck, Celera, Genomics PLC, San Therapeutics, Novartis, Sanofi, AstraZeneca, Alnylam, Eli Lilly, Leerink Partners, and Noble Insights. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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

U2 - 10.1016/j.jacc.2016.11.056

DO - 10.1016/j.jacc.2016.11.056

M3 - Article

C2 - 28209224

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

Abstract

Keywords

UN SDGs

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The Scottish eHealth Informatics Research Centre (E-HIRCs) (Joint with Universities of Aberdeen, Glasgow, Edinburgh, Strathclyde, St Andrews & Leicester and ISD)

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Doney, Alexander

Palmer, Colin

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