Association analyses based on false discovery rate implicate new loci for coronary artery disease.,Nature Genetics

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Association analyses based on false discovery rate implicate new loci for coronary artery disease.
Nature Genetics ( IF 31.7 ) Pub Date : 2017-07-17 , DOI: 10.1038/ng.3913
Christopher P Nelson _{1,

2} , Anuj Goel _{3,

4} , Adam S Butterworth _{5,

6} , Stavroula Kanoni _{7,

8} , Tom R Webb _{1,

2} , Eirini Marouli _{7,

8} , Lingyao Zeng ₉ , Ioanna Ntalla _{7,

8} , Florence Y Lai _{1,

2} , Jemma C Hopewell ₁₀ , Olga Giannakopoulou _{7,

8} , Tao Jiang ₅ , Stephen E Hamby _{1,

2} , Emanuele Di Angelantonio _{5,

6} , Themistocles L Assimes ₁₁ , Erwin P Bottinger ₁₂ , John C Chambers _{13,

14,

15} , Robert Clarke ₁₀ , Colin N A Palmer _{16,

17} , Richard M Cubbon ₁₈ , Patrick Ellinor ₁₉ , Raili Ermel ₂₀ , Evangelos Evangelou _{13,

21} , Paul W Franks _{22,

23,

24} , Christopher Grace _{3,

4} , Dongfeng Gu ₂₅ , Aroon D Hingorani ₂₆ , Joanna M M Howson ₅ , Erik Ingelsson ₂₇ , Adnan Kastrati ₉ , Thorsten Kessler ₉ , Theodosios Kyriakou _{3,

4} , Terho Lehtimäki ₂₈ , Xiangfeng Lu ₂₇ , Yingchang Lu _{12,

29} , Winfried März _{30,

31,

32} , Ruth McPherson ₃₃ , Andres Metspalu ₃₄ , Mar Pujades-Rodriguez ₃₅ , Arno Ruusalepp _{20,

36} , Eric E Schadt ₃₇ , Amand F Schmidt ₂₆ , Michael J Sweeting ₅ , Pierre A Zalloua _{38,

39} , Kamal AlGhalayini ₄₀ , Bernard D Keavney _{41,

42} , Jaspal S Kooner _{14,

15,

43} , Ruth J F Loos _{12,

44} , Riyaz S Patel _{45,

46} , Martin K Rutter _{47,

48} , Maciej Tomaszewski _{42,

49} , Ioanna Tzoulaki _{13,

21} , Eleftheria Zeggini ₅₀ , Jeanette Erdmann _{51,

52,

53} , George Dedoussis ₅₄ , Johan L M Björkegren _{36,

37,

55} , , , , Heribert Schunkert ₉ , Martin Farrall _{3,

4} , John Danesh _{5,

6,

56} , Nilesh J Samani _{1,

2} , Hugh Watkins _{3,

4} , Panos Deloukas _{7,

8,

57}

Affiliation

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK.
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
William Harvey Research Institute, Barts &the London Medical School, Queen Mary University of London, London, UK.
Centre for Genomic Health, Queen Mary University of London, London, UK.
German Heart Center Munich, Clinic at Technische Universität München and Deutsches Zentrum für Herz- und Kreislauferkrankungen (DZHK), partner site Munich Heart Alliance, Munich, Germany.
CTSU, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Southall, UK.
Imperial College Healthcare NHS Trust, London, UK.
Molecular and Clinical Medicine, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.
Pharmacogenomics Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.
Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.
Cardiac Arrhythmia Service and Cardiovascular Research Center, Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, Massachusetts, USA.
Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia.
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
Department of Clinical Sciences, Genetic &Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Lund University, Malmö, Sweden.
Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
Department of Public Health and Clinical Medicine, Unit of Medicine, Umeå University, Umeå, Sweden.
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Institute of Cardiovascular Science, University College London,London, UK.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
Medical Clinic V (Nephrology, Rheumatology, Hypertensiology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.
Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
Estonian Genome Center, University of Tartu, Tartu, Estonia.
Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK.
Clinical Gene Networks AB, Stockholm, Sweden.
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Lebanese American University, School of Medicine, Beirut, Lebanon.
Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK.
Mindich Child Health Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Farr Institute of Health Informatics, UCL, London, UK.
Bart's Heart Centre, St Bartholomew's Hospital, London, UK.
Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Manchester Diabetes Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
Division of Medicine, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
Wellcome Trust Sanger Institute, Hinxton, UK.
Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.
DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany.
University Heart Center Lübeck, Lübeck, Germany.
Department of Nutrition-Dietetics, Harokopio University, Athens, Greece.
Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden.
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.

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; ncases = 10,801) as well as a stricter definition without angina (HARD; ncases = 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.

中文翻译：

基于错误发现率的关联分析暗示了冠状动脉疾病的新位点。

在此分析时，冠状动脉疾病 (CAD) 的全基因组关联研究 (GWAS) 已鉴定出 66 个具有“全基因组显着性”(P < 5 × 10-8) 的位点，但假定的数量要多得多位点的错误发现率 (FDR) 为 5%（参考文献 1、2、3、4）。在这里，我们利用英国生物银行 (UKBB) 的临时发布数据来评估 FDR 方法的有效性。我们测试了包含心绞痛的 CAD 表型（软；n 例 = 10,801）以及更严格的无心绞痛定义（硬；n 例 = 6,482），并选择具有前一种表型的病例，使用两个最新的 CAD GWAS 进行荟萃分析。这种方法鉴定了 13 个具有全基因组意义的新基因座，其中 12 个位于我们之前满足 5% FDR 阈值的基因座列表中，从而为 FDR 鉴定的其余基因座代表真实信号提供了强有力的支持。本研究中与 5% FDR 相关的 304 个独立变异解释了 21.2% 的 CAD 遗传性，并确定了 243 个基因座，这些基因座涉及血管形态发生以及脂质代谢、一氧化氮信号传导和炎症的通路。

更新日期：2017-08-31

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