Hypertension (HT) or elevated blood pressure (BP) account for 13.5% of deaths worldwide. African Americans (AAs) experience higher rates of HT and related clinical consequences than European ancestry (EA) persons, as well as more severe HT with earlier age-of-onset, and these trends are maintained over the range of body mass index values. Racial differences in prevalence, incidence, and co morbidities are not explained by well- recognized risk factors and suggest etiological heterogeneity for elevated BP among AAs relative to EAs. Our group is leading the investigation of the genetic determinants of BP in African-ancestry populations with the Continental Origins and Genetic Epidemiology Network (COGENT) consortium. COGENT includes 24 cohorts with 39,397 participants with available genome-wide association study (GWAS) data. In a previous study of 19 studies with 29,378 participants we imputed using the HapMap Phase II data reference, we discovered 3 novel BP gene regions and refined 5 loci previously identified in the EA population. The International HapMap data consists of relatively common variants. It has been demonstrated that many low allele frequency variants with allele frequencies between 1-5% can be imputed with high quality using the 1000 Genomes Consortium reference haplotypes. This proposal extends our previous analysis by testing lower allele frequency variants that have not been previously evaluated for association with BP traits through recruiting additional AA cohorts, imputing genetic variants based on the 1000 Genomes Project reference, and state-of-art statistical approaches.
Our Specific Aims are: 1) Conduct a meta-analysis at individual SNPs of summary statistics from COGENT consortium cohorts using 1,000 Genomes-imputed GWAS data;2) Conduct variance component gene-based analyses using SKAT within each COGENT consortium cohort, and subsequent meta-analysis of results;3) Use individual level data and summary statistics from COGENT participants to evaluate whether recent selective sweeps on standing variation in known and novel BP loci contributes to the observed disparity in average BP between AA and EA populations. Our proposal is highly feasible, cost-efficient, powerful, and employs existing resources from the COGENT consortium collaboration and will represent the largest genetic study of BP in the AA population to date. Our team of investigators has experience participating in and leading large meta-analyses of cardiovascular traits and the equipment and facilities are in place to support this project. Included in our team will be an independent analysis group, tasked with independent verification of meta-analysis results. In addition, we will be able to accumulate a large sample size by utilizing existing resources to conduct the largest systematic investigation of BP determinants, fine mapping of BP mutations, and exploration of recent natural selection that may explain in part the disparities in BP traits consistently observed between EAs and AAs. This study has the potential to be an impactful study in the field of HT and BP genetics and will undoubtedly motivate R01 submissions to follow-up and fine-map identified gene regions.
Large scale genome-wide association studies (GWAS) of the genetic determinants of blood pressure in Europeans and Asians have discovered several gene regions with main effects on blood pressure, although effects have not been as well documented in African ancestry populations who are at increased risk for hypertension and related sequelae. We propose to coordinate and conduct a meta-analysis of African-ancestry GWAS for association with blood pressure in the ongoing Continental Origins and Genetic Epidemiology Network (COGENT) consortium, with a sample size of over 39,000 participants imputed to the 1000 Genomes reference haplotypes in the discovery stage. We will also investigate the relationship between gene-level variation and blood pressure with variant-collapsing methods, as well as evaluate the hypothesis that the demographic history of selection at blood pressure loci is responsible in part for the observed disparities in blood pressure traits between African and European populations.
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