title: 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.
authors.affiliation: Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA. xiaofeng.zhu@case.edu
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhu
authors.forename: J H
authors.initials: JH
authors.lastname: Young
authors.forename: Ervin
authors.initials: E
authors.lastname: Fox
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
authors.forename: Nora
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authors.lastname: Franceschini
authors.forename: Sunjung
authors.initials: S
authors.lastname: Kang
authors.forename: Bamidele
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authors.lastname: Tayo
authors.forename: Adebowale
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authors.lastname: Adeyemo
authors.forename: Yun V
authors.initials: YV
authors.lastname: Sun
authors.forename: Yali
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authors.lastname: Li
authors.forename: Alanna
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authors.lastname: Morrison
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Kiang
authors.initials: K
authors.lastname: Liu
authors.forename: Santhi K
authors.initials: SK
authors.lastname: Ganesh
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kutlar
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: Albert
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authors.lastname: Dreisbach
authors.forename: Sharon
authors.initials: S
authors.lastname: Wyatt
authors.forename: Joseph
authors.initials: J
authors.lastname: Polak
authors.forename: Walter
authors.initials: W
authors.lastname: Palmas
authors.forename: Solomon
authors.initials: S
authors.lastname: Musani
authors.forename: Herman
authors.initials: H
authors.lastname: Taylor
authors.forename: Richard
authors.initials: R
authors.lastname: Fabsitz
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Townsend
authors.forename: Daniel
authors.initials: D
authors.lastname: Dries
authors.forename: Joseph
authors.initials: J
authors.lastname: Glessner
authors.forename: Charleston W K
authors.initials: CW
authors.lastname: Chiang
authors.forename: Thomas
authors.initials: T
authors.lastname: Mosley
authors.forename: Sharon
authors.initials: S
authors.lastname: Kardia
authors.forename: David
authors.initials: D
authors.lastname: Curb
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Charles
authors.initials: C
authors.lastname: Rotimi
authors.forename: Alexander
authors.initials: A
authors.lastname: Reiner
authors.forename: Charles
authors.initials: C
authors.lastname: Eaton
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Richard S
authors.initials: RS
authors.lastname: Cooper
authors.forename: Susan
authors.initials: S
authors.lastname: Redline
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
mesh_terms: D001741:Black or African American / Q000235:genetics*; D001794:Blood Pressure / Q000235:genetics*; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D004268:DNA-Binding Proteins / Q000235:genetics; D003971:Diastole; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics; D013599:Systole; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C509201:SUB1 protein, human; D014157:Transcription Factors; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C