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Discovery and replication of novel blood pressure genetic loci in the Women's Genome Health Study.

ABSTRACT: OBJECTIVES:Genome-wide association meta-analyses have recently identified multiple loci associated with blood pressure. We sought to validate previously identified blood pressure loci by replication in a single large homogeneous population-based cohort and to identify new genome-wide significant loci using both conventional and expression-guided approaches. METHODS:We examined the associations of 18 single-nucleotide polymorphisms (SNPs) with genome-wide significance (P < 5.0 × 10??, 'primary'), and 13 suggestive SNPs (5.0 × 10?? < P < 5.6 × 10??, 'secondary'), all from previously established genome-wide association studies, with self-reported blood pressure in 23 019 women from the Women's Genome Health Study. We then targeted for replication 12 gene expression-associated SNPs (eSNPs) that were also previously associated with blood pressure phenotypes. RESULTS:Using these replication strategies, we found confirmatory evidence for 13/18 primary SNPs, 3/13 secondary SNPs, and 4/12 eSNPs in the Women's Genome Health Study. Meta-analysis combining the Women's Genome Health Study results with prior study results revealed one previously unrecognized blood pressure locus with genome-wide significance: a BLK-GATA4-adjacent region (P = 3.2 × 10??). CONCLUSION:In this analysis, conventional and eSNP-guided strategies were complementary and illustrate two ways for extending initial genome-wide association results for discovery of new genes involved in human disease. Using this strategy, we report a newly identified blood pressure locus, BLK-GATA4, that may further understanding of the complex genetic pathways regulating blood pressure.

SUBMITTER: Ho JE

PROVIDER: S-EPMC3005130 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Discovery and replication of novel blood pressure genetic loci in the Women's Genome Health Study.

Ho Jennifer E JE Levy Daniel D Rose Lynda L Johnson Andrew D AD Ridker Paul M PM Chasman Daniel I DI

Journal of hypertension 20110101 1

<h4>Objectives</h4>Genome-wide association meta-analyses have recently identified multiple loci associated with blood pressure. We sought to validate previously identified blood pressure loci by replication in a single large homogeneous population-based cohort and to identify new genome-wide significant loci using both conventional and expression-guided approaches.<h4>Methods</h4>We examined the associations of 18 single-nucleotide polymorphisms (SNPs) with genome-wide significance (P < 5.0 × 10 ...[more]

PMID: 21045733

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Project description:Sequencing of the human genome and decades of genetic association and linkage studies have dramatically improved our understanding of the etiology of many diseases. However, the multiple causes of complex diseases are still not well understood, in part because genetic and sociocultural risk factors are not typically investigated concurrently. Hypertension is a leading risk factor for cardiovascular disease and afflicts more African Americans than any other racially defined group in the US. Few genetic loci for hypertension have been replicated across populations, which may reflect population-specific differences in genetic variants and/or inattention to relevant sociocultural factors. Discrimination is a salient sociocultural risk factor for poor health and has been associated with hypertension. Here we use a biocultural approach to study blood pressure (BP) variation in African Americans living in Tallahassee, Florida by genotyping over 30,000 single nucleotide polymorphisms (SNPs) and capturing experiences of discrimination using novel measures of unfair treatment of self and others (n = 157). We perform a joint admixture and genetic association analysis for BP that prioritizes regions of the genome with African ancestry. We only report significant SNPs that were confirmed through our simulation analyses, which were performed to determine the false positive rate. We identify eight significant SNPs in five genes that were previously associated with cardiovascular diseases. When we include measures of unfair treatment and test for interactions between SNPs and unfair treatment, we identify a new class of genes involved in multiple phenotypes including psychosocial distress and mood disorders. Our results suggest that inclusion of culturally relevant stress measures, like unfair treatment in African Americans, may reveal new genes and biological pathways relevant to the etiology of hypertension, and may also improve our understanding of the complexity of gene-environment interactions that underlie complex diseases.

Dataset Information

Discovery and replication of novel blood pressure genetic loci in the Women's Genome Health Study.

Publications

Discovery and replication of novel blood pressure genetic loci in the Women's Genome Health Study.

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