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

Xiaofeng Zhu, J H Young, Ervin Fox, Brendan J Keating, Nora Franceschini, Sunjung Kang, Bamidele Tayo, Adebowale Adeyemo, Yun V Sun, Yali Li, Alanna Morrison, Christopher Newton-Cheh, Kiang Liu, Santhi K Ganesh, Abdullah Kutlar, Ramachandran S Vasan, Albert Dreisbach, Sharon Wyatt, Joseph Polak, Walter Palmas, Solomon Musani, Herman Taylor, Richard Fabsitz, Raymond R Townsend, Daniel Dries, Joseph Glessner, Charleston W K Chiang, Thomas Mosley, Sharon Kardia, David Curb, Joel N Hirschhorn, Charles Rotimi, Alexander Reiner, Charles Eaton, Jerome I Rotter, Richard S Cooper, Susan Redline, Aravinda Chakravarti, Daniel Levy
Human Molecular Genetics 2011 June 1, 20 (11): 2285-95
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.


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