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

Publication ,  Journal Article
Webb, TR; Erdmann, J; Stirrups, KE; Stitziel, NO; Masca, NGD; Jansen, H; Kanoni, S; Nelson, CP; Ferrario, PG; König, IR; Eicher, JD; Hamby, SE ...
Published in: J Am Coll Cardiol
February 21, 2017

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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Published In

J Am Coll Cardiol

DOI

EISSN

1558-3597

Publication Date

February 21, 2017

Volume

69

Issue

7

Start / End Page

823 / 836

Location

United States

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Odds Ratio
  • Male
  • Humans
  • Genome-Wide Association Study
  • Genetic Pleiotropy
  • Genetic Loci
  • Gene Frequency
  • Female
  • Coronary Artery Disease
 

Citation

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Webb, T. R., Erdmann, J., Stirrups, K. E., Stitziel, N. O., Masca, N. G. D., Jansen, H., … Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators, . (2017). Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease. J Am Coll Cardiol, 69(7), 823–836. https://doi.org/10.1016/j.jacc.2016.11.056
Webb, Thomas R., Jeanette Erdmann, Kathleen E. Stirrups, Nathan O. Stitziel, Nicholas G. D. Masca, Henning Jansen, Stavroula Kanoni, et al. “Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease.J Am Coll Cardiol 69, no. 7 (February 21, 2017): 823–36. https://doi.org/10.1016/j.jacc.2016.11.056.
Webb TR, Erdmann J, Stirrups KE, Stitziel NO, Masca NGD, Jansen H, et al. Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease. J Am Coll Cardiol. 2017 Feb 21;69(7):823–36.
Webb, Thomas R., et al. “Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease.J Am Coll Cardiol, vol. 69, no. 7, Feb. 2017, pp. 823–36. Pubmed, doi: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 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, Hoffmann P, Holmen OL, Hveem K, Jansson J-H, Jöckel K-H, 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, Wellcome Trust Case Control Consortium, Zeng L, Chowdhury R, Salomaa V, Ford I, Jukema JW, Amouyel P, Kontto J, MORGAM Investigators, 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 J-C, Thompson JR, Wareham NJ, Watkins H, Willer CJ, Samani NJ, Schunkert H, Deloukas P, Kathiresan S, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease. J Am Coll Cardiol. 2017 Feb 21;69(7):823–836.
Journal cover image

Published In

J Am Coll Cardiol

DOI

EISSN

1558-3597

Publication Date

February 21, 2017

Volume

69

Issue

7

Start / End Page

823 / 836

Location

United States

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Odds Ratio
  • Male
  • Humans
  • Genome-Wide Association Study
  • Genetic Pleiotropy
  • Genetic Loci
  • Gene Frequency
  • Female
  • Coronary Artery Disease