Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Hum Mol Genet. 2011 Jun 1;20(11):2285-95. doi: 10.1093/hmg/ddr113. Epub 2011 Mar 21.
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.
基于最近混合人群的混合映射分析是一种强大的方法,可以检测到在祖先人群中具有显著等位基因频率差异的疾病变体。我们对 6303 名无关的非裔美国人参与者进行了收缩压(SBP)和舒张压(DBP)的混合映射分析,随后进行了特征-标记关联分析,该参与者来自候选基因关联资源(CARe)联盟。我们确定了五个基因组区域(P<0.001),其中包含导致个体间 BP 变异的遗传变异。在后续的关联分析中,对本研究中进行的所有测试进行校正后,三个基因座与 SBP 显著相关,一个与 DBP 显著相关(P<10(-5))。进一步的分析表明,六个独立的单核苷酸多态性(SNP)导致了混合映射分析中观察到的表型变异。在对非裔美国人的多个大型独立研究(妇女健康倡议(WHI)、梅伍德、动脉病遗传流行病学网络(GENOA)和霍华德大学家庭研究(HUFS))以及一个非洲本地样本(尼日利亚研究)进行的重复分析中,检查了这六个 SNP 的复制情况,复制样本总大小为 11882 个。对重复样本的荟萃分析确定了 SUB1 和 NPR3 基因之间染色体 5 上的一个新变体(rs7726475)与 SBP 和 DBP 相关(两者的 P 值均<0.0015);在将 CARe 样本与复制数据进行荟萃分析时,我们观察到 rs7726475 与 SBP 的 P 值为 4.45×10(-7),与 DBP 的 P 值为 7.52×10(-7),在考虑到所有测试后,这些 P 值均具有统计学意义。我们的研究表明,混合映射分析可以帮助识别由于全基因组中测试数量急剧减少而被全基因组关联研究遗漏的遗传变异。