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

Wellcome Trust Case Control Consortium; 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; Thorsten Kessler; Thomas F Vogt; Wolfgang Lieb; Heribert Schunkert

doi:10.1016/j.jacc.2016.11.056

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

Wellcome Trust Case Control Consortium, 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 WeekePaul 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, Thorsten Kessler, Thomas F Vogt, Wolfgang Lieb, Heribert Schunkert

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.

Originalsprache	Englisch
Zeitschrift	Journal of the American College of Cardiology
Jahrgang	69
Ausgabenummer	7
Seiten (von - bis)	823-836
Seitenumfang	14
ISSN	0735-1097
DOIs	https://doi.org/10.1016/j.jacc.2016.11.056
Publikationsstatus	Veröffentlicht - 21.02.2017

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10.1016/j.jacc.2016.11.056

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Wellcome Trust Case Control Consortium, 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., ... Schunkert, H. (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{6360eafec9ec465f87500eaaf6f1fa8c,

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.",

author = "{Wellcome Trust Case Control Consortium} and 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 Thorsten Kessler and Vogt, {Thomas F} and Wolfgang Lieb and Heribert Schunkert",

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",

number = "7",

}

Wellcome Trust Case Control Consortium, 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, Kessler, T, Vogt, TF, Lieb, W & Schunkert, H 2017, 'Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease', Journal of the American College of Cardiology, Jg. 69, Nr. 7, S. 823-836. https://doi.org/10.1016/j.jacc.2016.11.056

Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease. / Wellcome Trust Case Control Consortium; Webb, Thomas R; Erdmann, Jeanette et al.
in: Journal of the American College of Cardiology, Jahrgang 69, Nr. 7, 21.02.2017, S. 823-836.

Publikation: Beiträge in Fachzeitschriften › Zeitschriftenaufsätze › Forschung › Begutachtung

TY - JOUR

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

AU - Wellcome Trust Case Control Consortium

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 - Kessler, Thorsten

AU - Vogt, Thomas F

AU - Lieb, Wolfgang

AU - Schunkert, Heribert

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.

U2 - 10.1016/j.jacc.2016.11.056

DO - 10.1016/j.jacc.2016.11.056

M3 - Journal articles

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

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