TY - JOUR
T1 - Combined admixture mapping and association analysis identifies a novel blood pressure genetic locus on 5p13
T2 - Contributions from the CARe consortium
AU - Zhu, Xiaofeng
AU - Young, J. H.
AU - Fox, Ervin
AU - Keating, Brendan J.
AU - Franceschini, Nora
AU - Kang, Sunjung
AU - Tayo, Bamidele
AU - Adeyemo, Adebowale
AU - Sun, Yun V.
AU - Li, Yali
AU - Morrison, Alanna
AU - Newton-Cheh, Christopher
AU - Liu, Kiang
AU - Ganesh, Santhi K.
AU - Kutlar, Abdullah
AU - Vasan, Ramachandran S.
AU - Dreisbach, Albert
AU - Wyatt, Sharon
AU - Polak, Joseph
AU - Palmas, Walter
AU - Musani, Solomon
AU - Taylor, Herman
AU - Fabsitz, Richard
AU - Townsend, Raymond R.
AU - Dries, Daniel
AU - Glessner, Joseph
AU - Chiang, Charleston W.K.
AU - Mosley, Thomas
AU - Kardia, Sharon
AU - Curb, David
AU - Hirschhorn, Joel N.
AU - Rotimi, Charles
AU - Reiner, Alexander
AU - Eaton, Charles
AU - Rotter, Jerome I.
AU - Cooper, Richard S.
AU - Redline, Susan
AU - Chakravarti, Aravinda
AU - Levy, Daniel
N1 - Funding Information:
Maywood African-American and Nigeria studies are supported by the National Institutes of Health, grant numbers HL074166 and HL53353 from the National Heart, Lung, and Blood Institute. Y.L. and X.Z. are supported by HL086718 from the National Heart, Lung, and Blood Institute and HG003054 from the National Human Genome Research Institute.
Funding Information:
Genetic Epidemiology Network of Arteriopathy (GENOA) study is supported by the National Institutes of Health, grant numbers HL087660 and HL100245 from the National Heart, Lung, and Blood Institute.
Funding Information:
The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100 – 32102, 32105, 32106, 32108 – 32109, 32111 – 32113, 32115, 32118, 32119, 32122, 42107 – 42126, 42129 – 42132, and 44221.
PY - 2011/6
Y1 - 2011/6
N2 - 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 genomewide association studies because of drastically reduced number of tests in the whole genome.
AB - 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 genomewide association studies because of drastically reduced number of tests in the whole genome.
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U2 - 10.1093/hmg/ddr113
DO - 10.1093/hmg/ddr113
M3 - Article
C2 - 21422096
AN - SCOPUS:79955989635
SN - 0964-6906
VL - 20
SP - 2285
EP - 2295
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 11
M1 - ddr113
ER -