Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries

Abstract

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

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Affiliated Institutions

• Institute of Genetics and Cancer GB
• National Center for Global Health and Medicine JP
• Harvard University US
• UCLA Medical Center US
• University of Dundee GB
• Tampere University Hospital FI
• Agency for Science, Technology and Research SG
• Johns Hopkins Medicine US
• University of Regensburg DE
• Ninewells Hospital GB
• Singapore Eye Research Institute SG
• Harbor–UCLA Medical Center US
• National University of Singapore SG
• Medical Research Council GB
• Helmholtz Zentrum München DE
• University of Groningen NL
• Universidade de São Paulo BR
• Genome Institute of Singapore SG
• Baylor Genetics US
• University of North Carolina at Chapel Hill US
• Wake Forest University US
• Karolinska Institutet SE
• University of Edinburgh GB
• National Human Genome Research Institute US
• Massachusetts General Hospital US
• Centre National de la Recherche Scientifique FR
• Pennington Biomedical Research Center US
• University of Leicester GB
• National University Health System SG
• University of Mississippi Medical Center US
• Centre for Human Genetics GB
• The Lundquist Institute US
• Imperial College London GB
• University of Trieste IT
• Universität Greifswald DE
• Huazhong University of Science and Technology CN
• Michigan United US
• Ealing Hospital GB
• University of Kelaniya LK
• Loyola University Chicago US
• Brigham and Women's Hospital US
• Duke-NUS Medical School SG
• Université de Lille FR
• Edinburgh Cancer Research GB
• SIB Swiss Institute of Bioinformatics CH
• University of Cambridge GB
• The University of Texas Health Science Center at Houston US
• Leiden University Medical Center NL
• National Institute on Aging US
• Case Western Reserve University US
• Brown Foundation US
• Universidade Federal de Pelotas BR
• Brown University US
• Boston University US
• University of Oxford GB
• Lund University SE
• University Medical Center Groningen NL
• Glenfield Hospital GB
• Erasmus MC NL
• Baylor College of Medicine US
• Tampere University FI
• University of Georgia US
• University of Bristol GB
• National Institutes of Health US
• University of Iceland IS
• European Genomic Institute for Diabetes FR
• Icelandic Heart Association IS
• University of Glasgow GB
• RIKEN Center for Integrative Medical Sciences JP
• Medical College of Wisconsin US
• Circadian (United States) US
• University of Eastern Finland FI
• Singapore National Eye Center SG
• Skåne University Hospital SE
• William Harvey Research Institute GB
• Queen Mary University of London GB
• Institut Pasteur de Lille FR
• Jackson Memorial Hospital US
• University of Michigan US
• NIHR Leicester Biomedical Research Centre GB
• University Hospital of Geneva CH
• MRC Epidemiology Unit GB
• Vanderbilt University US
• Institut Pasteur FR
• University of Washington US
• University of Tartu EE
• Johns Hopkins University US
• Washington University in St. Louis US
• German Centre for Cardiovascular Research DE
• University of Lausanne CH

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