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 Schadt; Paul L Auer; Johan L M Björkegren; Peter Ejvin Weeke; Ursula M Schick; Yingchang Lu; He Zhang; Marie-Pierre Dubé; Anuj Goel; Martin Farrall; Gina M Peloso; Hong-Hee Won; Ron Do; Erik P A 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 Angelica Merlini; Stefano Duga; Nicola Marziliano; Josh C Denny; Christian M Shaffer; Nour Eddine El Mokhtari; Andre Franke; Stefanie Heilmann-Heimbach; Christian Hengstenberg; Per Hoffmann; Børge G Nordestgaard; Wellcome Trust Case Control Consortium

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 Schadt, Paul L Auer, Johan L M Björkegren, Peter Ejvin WeekeUrsula M Schick, Yingchang Lu, He Zhang, Marie-Pierre Dubé, Anuj Goel, Martin Farrall, Gina M Peloso, Hong-Hee Won, Ron Do, Erik P A 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 Angelica Merlini, Stefano Duga, Nicola Marziliano, Josh C Denny, Christian M Shaffer, Nour Eddine El Mokhtari, Andre Franke, Stefanie Heilmann-Heimbach, Christian Hengstenberg, Per Hoffmann, Børge G Nordestgaard, Wellcome Trust Case Control Consortium

Department of Clinical Medicine

114 Citations (Scopus)

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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
Journal	Journal of the American College of Cardiology
Volume	69
Issue number	7
Pages (from-to)	823-836
Number of pages	14
ISSN	0735-1097
DOIs	https://doi.org/10.1016/j.jacc.2016.11.056
Publication status	Published - 21 Feb 2017

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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., Auer, P. L., Björkegren, J. L. M., ... Wellcome Trust Case Control Consortium (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

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, E, Auer, PL, Björkegren, JLM, Weeke, PE, Schick, UM, Lu, Y, Zhang, H, Dubé, M-P, Goel, A, Farrall, M, Peloso, GM, Won, H-H, Do, R, van Iperen, EPA, Kruppa, J, Mahajan, A, Scott, RA, Willenborg, C, Braund, PS, van Capelleveen, JC, Doney, ASF, Donnelly, LA, Asselta, R, Angelica Merlini, P, Duga, S, Marziliano, N, Denny, JC, Shaffer, CM, El Mokhtari, NE, Franke, A, Heilmann-Heimbach, S, Hengstenberg, C, Hoffmann, P, Nordestgaard, BG & Wellcome Trust Case Control Consortium 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

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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.",

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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 Eric Schadt and Auer, {Paul L} and Bj{\"o}rkegren, {Johan L M} and Weeke, {Peter Ejvin} and Schick, {Ursula M} and Yingchang Lu and He Zhang and Marie-Pierre Dub{\'e} and Anuj Goel and Martin Farrall and Peloso, {Gina M} and Hong-Hee Won and Ron Do and {van Iperen}, {Erik P A} 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 {Angelica Merlini}, Pier and Stefano Duga and Nicola Marziliano and Denny, {Josh C} and Shaffer, {Christian M} and {El Mokhtari}, {Nour Eddine} and Andre Franke and Stefanie Heilmann-Heimbach and Christian Hengstenberg and Per Hoffmann and Nordestgaard, {B{\o}rge G} and {Wellcome Trust Case Control Consortium}",

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

language = "English",

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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

AU - Auer, Paul L

AU - Björkegren, Johan L M

AU - Weeke, Peter Ejvin

AU - Schick, Ursula M

AU - Lu, Yingchang

AU - Zhang, He

AU - Dubé, Marie-Pierre

AU - Goel, Anuj

AU - Farrall, Martin

AU - Peloso, Gina M

AU - Won, Hong-Hee

AU - Do, Ron

AU - van Iperen, Erik P A

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 - Angelica Merlini, Pier

AU - Duga, Stefano

AU - Marziliano, Nicola

AU - Denny, Josh C

AU - Shaffer, Christian M

AU - El Mokhtari, Nour Eddine

AU - Franke, Andre

AU - Heilmann-Heimbach, Stefanie

AU - Hengstenberg, Christian

AU - Hoffmann, Per

AU - Nordestgaard, Børge G

AU - Wellcome Trust Case Control Consortium

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 - Journal Article

U2 - 10.1016/j.jacc.2016.11.056

DO - 10.1016/j.jacc.2016.11.056

M3 - Journal 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 -