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

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Christopher P Nelson
  • Anuj Goel
  • Adam S Butterworth
  • Stavroula Kanoni
  • Tom R. Webb
  • Eirini Marouli
  • Lingyao Zeng
  • Ioanna Ntalla
  • Florence Y. Lai
  • Jemma C Hopewell
  • Olga Giannakopoulou
  • Tao Jiang
  • Stephen E. Hamby
  • Emanuele Di Angelantonio
  • Themistocles L Assimes
  • Erwin P Bottinger
  • John C Chambers
  • Robert Clarke
  • Colin N. A. Palmer
  • Richard M. Cubbon
  • Patrick T Ellinor
  • Raili Ermel
  • Evangelos Evangelou
  • Christopher Grace
  • Dongfeng Gu
  • Aroon D Hingorani
  • Joanna M. M. Howson
  • Erik Ingelsson
  • Adnan Kastrati
  • Thorsten Kessler
  • Theodosios Kyriakou
  • Terho Lehtimäki
  • Xiangfeng Lu
  • Yingchang Lu
  • Winfried März
  • Ruth McPherson
  • Andres Metspalu
  • Mar Pujades-Rodriguez
  • Arno Ruusalepp
  • Eric Schadt
  • Amand F. Schmidt
  • Michael J. Sweeting
  • Pierre A. Zalloua
  • Kamal Alghalayini
  • Bernard D. Keavney
  • Jaspal S Kooner
  • Ruth J F Loos
  • Riyaz S. Patel
  • Martin K. Rutter
  • Maciej Tomaszewski
  • Ioanna Tzoulaki
  • Eleftheria Zeggini
  • Jeanette Erdmann
  • George Dedoussis
  • Johan L M Björkegren
  • Heribert Schunkert
  • Martin Farrall
  • John Danesh
  • Nilesh J. Samani
  • Hugh Watkins
  • Panos Deloukas
Organisations
External organisations
  • University of Leicester
  • University of Oxford
  • Wellcome Trust Centre for Human Genetics
  • University of Cambridge
  • Queen Mary University
  • Technical University of Munich
  • Stanford University
  • Icahn School of Medicine at Mount Sinai
  • Imperial College London
  • Ealing Hospital
  • Ninewells Hospital and Medical School
  • University of Leeds
  • Massachusetts Institute of Technology
  • Tartu University Hospital
  • University of Ioannina
  • Harvard University
  • Umeå University
  • National Center for Cardiovascular Diseases
  • University College London
  • University of Tampere
  • Medical University of Graz
  • Heidelberg University
  • University of Ottawa
  • University of Tartu
  • Lebanese American University
  • King Abdulaziz University
  • University of Manchester
  • St Bartholomew's Hospital
  • Wellcome Trust Sanger Institute
  • German Centre for Cardiovascular Research
  • Harokopio University
  • Karolinska University Hospital
  • Wellcome Trust Genome Campus
  • NIHR Biomedical Research Centre, Leicester
  • University of Dundee
  • Broad Institute
  • Skåne University Hospital
  • Peking Union Medical College
  • Vanderbilt University
  • Synlab Holding Germany GmbH
  • Clinical Gene Networks AB
  • Central Manchester University Hospitals
  • University of Lübeck
  • Karolinska Institutet
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Cardiac and Cardiovascular Systems
Original languageEnglish
Pages (from-to)1385-1391
Number of pages7
JournalNature Genetics
Volume49
Issue number9
Publication statusPublished - 2017 Sep 1
Publication categoryResearch
Peer-reviewedYes