A comprehensive 1000 Genomes–based genome-wide association meta-analysis of coronary artery disease · SciRah

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A comprehensive 1000 Genomes–based genome-wide association meta-analysis of coronary artery disease

Majid Nikpay^a, Alexandre F.R. Stewart^a, Ruth McPherson^a✉, Anuj Goel^{b c}, Theodosios Kyriakou^{b c}, Christopher Grace^{b c}, Shapour Jalilzadeh^{b c}, Hugh C Watkins^{b c}✉, Martin Farrall^{b c}✉, Natalie R. van Zuydam^{c d},

Nature Genetics Nature Portfolio2015-09-07 2,444 citations84 references

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Abstract

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

TL;DRA GWAS meta-analysis of CAD cases and controls provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size. (Semantic Scholar)

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Discussion

^aRuddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada
^bDivision of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
^cWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
^dMedical Research Institute, University of Dundee, Dundee, UK
^eBroad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA
^fDepartment of Biostatistics, University of Liverpool, Liverpool, UK
^gDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA
^hMolecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
ⁱScience for Life Laboratory, Uppsala University, Uppsala, Sweden
^jCardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA
^kCenter for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA
^lDepartment of Medicine, Harvard Medical School, Boston, Massachusetts, USA
^mDepartment of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
ⁿDepartment of Genetics, Harvard Medical School, Boston, Massachusetts, USA
^oDivision of Endocrinology and Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA
^pEstonian Genome Center, University of Tartu, Tartu, Estonia
^qDepartment of Cardiovascular Sciences, University of Leicester, Leicester, UK
^rNIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK
^sDZHK (German Research Center for Cardiovascular Research) partner site Hamburg-Lübeck-Kiel, Lübeck, Germany
^tInstitut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany
^uInstitut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany
^vWilliam Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
^wDepartment of Haematology, University of Cambridge, Cambridge, UK
^xPrincess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia
^yCenter for Non-Communicable Diseases, Karachi, Pakistan
^zPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
✉Corresponding author