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Association analyses based on false discovery rate implicate new loci for coronary artery disease

Nelson, Christopher P; Goel, Anuj; Butterworth, Adam S; Kanoni, Stavroula; Webb, Tom R.; Marouli, Eirini; Zeng, Lingyao; Ntalla, Ioanna; Lai, Florence Y. and Hopewell, Jemma C, et al. (2017) In Nature Genetics 49(9). p.1385-1391
Abstract

Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10 '8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n cases = 10,801) as well as a stricter definition without angina (HARD; n cases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci... (More)

Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10 '8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n cases = 10,801) as well as a stricter definition without angina (HARD; n cases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.

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Nature Genetics
volume
49
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9
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7 pages
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Nature Publishing Group
external identifiers
  • scopus:85028693072
  • wos:000408672000017
ISSN
1061-4036
DOI
10.1038/ng.3913
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English
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yes
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b4a38aa0-2e30-43e6-85c2-9d566835bff9
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2017-09-27 07:53:30
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2018-10-16 03:23:29
@article{b4a38aa0-2e30-43e6-85c2-9d566835bff9,
  abstract     = {<p>Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P &lt; 5 × 10 '8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n cases = 10,801) as well as a stricter definition without angina (HARD; n cases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.</p>},
  author       = {Nelson, Christopher P and Goel, Anuj and Butterworth, Adam S and Kanoni, Stavroula and Webb, Tom R. and Marouli, Eirini and Zeng, Lingyao and Ntalla, Ioanna and Lai, Florence Y. and Hopewell, Jemma C and Giannakopoulou, Olga and Jiang, Tao and Hamby, Stephen E. and Di Angelantonio, Emanuele and Assimes, Themistocles L and Bottinger, Erwin P and Chambers, John C and Clarke, Robert and Palmer, Colin N. A. and Cubbon, Richard M. and Ellinor, Patrick T and Ermel, Raili and Evangelou, Evangelos and Franks, Paul W. and Grace, Christopher and Gu, Dongfeng and Hingorani, Aroon D and Howson, Joanna M. M. and Ingelsson, Erik and Kastrati, Adnan and Kessler, Thorsten and Kyriakou, Theodosios and Lehtimäki, Terho and Lu, Xiangfeng and Lu, Yingchang and März, Winfried and McPherson, Ruth and Metspalu, Andres and Pujades-Rodriguez, Mar and Ruusalepp, Arno and Schadt, Eric and Schmidt, Amand F. and Sweeting, Michael J. and Zalloua, Pierre A. and Alghalayini, Kamal and Keavney, Bernard D. and Kooner, Jaspal S and Loos, Ruth J F and Patel, Riyaz S. and Rutter, Martin K. and Tomaszewski, Maciej and Tzoulaki, Ioanna and Zeggini, Eleftheria and Erdmann, Jeanette and Dedoussis, George and Björkegren, Johan L M and Schunkert, Heribert and Farrall, Martin and Danesh, John and Samani, Nilesh J. and Watkins, Hugh and Deloukas, Panos},
  issn         = {1061-4036},
  language     = {eng},
  month        = {09},
  number       = {9},
  pages        = {1385--1391},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Association analyses based on false discovery rate implicate new loci for coronary artery disease},
  url          = {http://dx.doi.org/10.1038/ng.3913},
  volume       = {49},
  year         = {2017},
}