Combined admixture mapping and association analysis identifies a novel blood pressure genetic locus on 5p13: contributions from the CARe consortium

Abstract

Admixture mapping based on recently admixed populations is a powerful method to detect disease variants with substantial allele frequency differences in ancestral populations. We performed admixture mapping analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP), followed by trait-marker association analysis, in 6303 unrelated African-American participants of the Candidate Gene Association Resource (CARe) consortium. We identified five genomic regions (P< 0.001) harboring genetic variants contributing to inter-individual BP variation. In follow-up association analyses, correcting for all tests performed in this study, three loci were significantly associated with SBP and one significantly associated with DBP (P< 10(-5)). Further analyses suggested that six independent single-nucleotide polymorphisms (SNPs) contributed to the phenotypic variation observed in the admixture mapping analysis. These six SNPs were examined for replication in multiple, large, independent studies of African-Americans [Women's Health Initiative (WHI), Maywood, Genetic Epidemiology Network of Arteriopathy (GENOA) and Howard University Family Study (HUFS)] as well as one native African sample (Nigerian study), with a total replication sample size of 11 882. Meta-analysis of the replication set identified a novel variant (rs7726475) on chromosome 5 between the SUB1 and NPR3 genes, as being associated with SBP and DBP (P< 0.0015 for both); in meta-analyses combining the CARe samples with the replication data, we observed P-values of 4.45 × 10(-7) for SBP and 7.52 × 10(-7) for DBP for rs7726475 that were significant after accounting for all the tests performed. Our study highlights that admixture mapping analysis can help identify genetic variants missed by genome-wide association studies because of drastically reduced number of tests in the whole genome.

Advances in Blood Pressure Genomics

“…19,[37][38][39][40][41][42] Some studies have suggested that the effect sizes of blood pressure variants may differ between different ethnic groups, (eg, the FGF5 locus). 41 The ICBP-GWAS study performed a comprehensive analysis of whether findings made in people of European ancestry can be extended to individuals of non-European origin.…”

Socioeconomic Position, But Not African Genomic Ancestry, Is Associated With Blood Pressure in the Bambui-Epigen (Brazil) Cohort Study of Aging

“…[1][2][3][4] Studying this relationship in Latin America-and in Brazil specifically-offers several opportunities because it is one of the most ethnoracially heterogeneous regions of the world. 5,6 Life expectancy has increased rapidly in the region, 7 generating populations with unprecedented numbers of admixed older persons at risk of hypertension.…”

Genetics and Genomics for the Prevention and Treatment of Cardiovascular Disease: Update

“…GWASs in non-European ancestry individuals have also been performed, but fewer loci have been discovered and even fewer have been replicated, likely because of their much smaller sample sizes. 98,102,108,109 This difference may result from low statistical power and not genetic heterogeneity because the 29 International Consortium of Blood Pressure loci discovered in European individuals have been demonstrated to jointly have highly significant effects in African, East Asian, and South Asian individuals (Table 3). 94 Genomic studies of BP and hypertension have also been extended to other useful surrogates.…”