Discovery and replication of novel blood pressure genetic loci in the Women's Genome Health Study.
Discovery and replication of novel blood pressure genetic loci in the Women's Genome Health Study.
复制标题
DOI：
10.1097/hjh.0b013e3283406927
复制
发表时间：
2011-01
影响因子：
4.9
通讯作者：
Chasman DI
中科院分区：
文献类型：
--
作者：
Ho JE;Levy D;Rose L;Johnson AD;Ridker PM;Chasman DI
全基因组关联荟萃分析最近发现了多个与血压相关的基因座。我们试图通过在单个大型同质人群队列中复制来验证先前鉴定的血压基因座，并使用传统和表达引导方法鉴定新的全基因组显著基因座。我们检查了18个具有全基因组意义的snp （P < 5.0 × 10−8，“主要”）和13个暗含性snp （5.0 × 10−8 < P < 2.6 × 10−5，“次要”）的相关性，这些snp均来自先前建立的全基因组关联研究，与来自女性基因组健康研究的23,019名女性的自我报告血压有关。然后，我们瞄准了12个基因表达相关snp （eSNPs）的复制，这些snp之前也与血压表型相关。使用这些复制策略，我们在女性基因组健康研究中发现了13/18个初级snp， 3/13个次级snp和4/12个eSNPs的确凿证据。将女性基因组健康研究结果与先前的研究结果相结合的荟萃分析揭示了一个以前未被认识到的具有全基因组意义的血压位点：blk - gata4邻近区域（P = 3.2 × 10−8）。在本分析中，常规策略和esnp指导策略是互补的，并说明了扩展初始全基因组关联结果以发现与人类疾病有关的新基因的两种方法。使用这种策略，我们报告了一个新发现的血压位点BLK-GATA4，它可能进一步了解调节血压的复杂遗传途径。
Genome-wide association meta-analyses have recently identified multiple loci associated with blood pressure. We sought to validate previously identified blood pressure loci by replication in a single large homogenous population-based cohort, and to identify new genome-wide significant loci using both conventional and expression-guided approaches. We examined the associations of 18 SNPs with genome-wide significance (P < 5.0 × 10−8, ‘primary’), and 13 suggestive SNPs (5.0 × 10−8 < P < 2.6 × 10−5, ‘secondary’), all from previously established genome-wide association studies, with self-reported blood pressure in 23,019 women from the Women’s Genome Health Study. We then targeted for replication 12 gene expression-associated SNPs (eSNPs) that were also previously associated with blood pressure phenotypes. Using these replication strategies, we found confirmatory evidence for 13/18 primary SNPs, 3/13 secondary SNPs, and 4/12 eSNPs in the Women’s Genome Health Study. Meta-analysis combining the Women’s Genome Health Study results with prior study results revealed one previously unrecognized blood pressure locus with genome-wide significance: a BLK-GATA4-adjacent region (P = 3.2 × 10−8). In this analysis, conventional and eSNP-guided strategies were complementary and illustrate two ways for extending initial genome-wide association results for discovery of new genes involved in human disease. Using this strategy, we report a newly identified blood pressure locus, BLK-GATA4, that may further understanding of the complex genetic pathways regulating blood pressure.