title: Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.
abstract: We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
authors.affiliation: Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
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authors.forename: Nina
authors.initials: N
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authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.|Department of Medicine I, Ludwig Maximilians University Munich, Munich, Germany.|German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
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authors.affiliation: Bioinformatics Division, Tsinghua National Laboratory for Informatics Science and Technology (TNLIST), Ministry of Education Key Laboratory of Bioinformatics, Department of Automation, Tsinghua University, Beijing, China.|Center for Synthetic and Systems Biology, TNLIST, Ministry of Education Key Laboratory of Bioinformatics, Department of Automation, Tsinghua University, Beijing, China.|Department of Psychiatry, University of Hong Kong, Hong Kong.
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authors.affiliation: Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
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authors.initials: YT
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authors.initials: X
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authors.initials: A
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authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Karen L
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authors.initials: DK
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authors.affiliation: Vanderbilt Epidemiology Center, Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, USA.|Vanderbilt-Ingram Cancer Center, Division of Epidemiology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
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authors.initials: JBJ
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authors.initials: AR
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authors.affiliation: Vanderbilt Epidemiology Center, Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, USA.|Vanderbilt-Ingram Cancer Center, Division of Epidemiology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
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authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
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authors.affiliation: Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.
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authors.affiliation: Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
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authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.|Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.|Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.|Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute of the Netherlands (ICIN)-Netherlands Heart Institute, Utrecht, the Netherlands.
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authors.affiliation: Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK.|National Heart and Lung Institute, Imperial College London, London, UK.|Imperial College Healthcare NHS Trust, London, UK.
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authors.initials: JS
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authors.affiliation: Department of Epidemiology and Biostatistics, Imperial College London, London, UK.|Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK.|Imperial College Healthcare NHS Trust, London, UK.
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mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000097:blood / Q000208:ethnology / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain