Rare Variants for Hypertension in Taiwan Chinese

描述（由申请人提供）：高血压及其后遗症构成了一个主要的公共卫生负担，因此，确定高血压的因果变异可能导致开发新的干预措施来控制或治疗不良结局。虽然全基因组关联研究（GWAS）已经成功地确定了29种常见的高血压变异，但它们的影响共同解释了不到2.5%的血压（BP） 方差，大部分遗传力仍然缺失。我们提出了一个全面的研究，以确定罕见的和低频率的变异，据说更大的影响高血压和高血压在高度丰富的台湾中国高血压家族使用全外显子测序和国家的最先进的统计方法。 SAPPHIRe网络在家庭血压计划（FBPP）招募台湾家庭与多个高血压同胞。因此，通过研究的设计，家庭样本高度富集高血压和BP分离变体。我们发现，这种类型的招聘和进一步选择的一个子集的家庭与强大的连锁证据大大丰富了罕见的和低频率的变异高血压/BP相比，一般人群的几倍。因此，我们建议在150个高度富集的台湾同胞对（300名受试者）和300名来自台湾的无关对照中进行外显子组测序，并对所有SAPPHIRe家族（N= 1，200）和1，200名无关匹配对照中的前6，000个SNP进行基因分型。最后，与高血压/BP最相关的50种变异将在大型多种族队列中复制，包括中国和美国人群，近45，000例受试者。这项研究可以潜在地解释很大一部分缺失的遗传性，这可能导致重要的转化研究，具有相当大的公共卫生意义。因此，潜在影响非常大。 公共卫生相关性：本研究的主要目的是通过对150对高度富集的中国台湾同胞进行外显子组测序，鉴定对血压和高血压有较大影响的罕见和低频变异（300名受试者）和300名无关对照，然后在更大的样本中验证前6,000个SNP，最后在近45个样本中复制前50个SNP，000多个民族。高血压的任何成功都可能导致具有相当公共卫生意义的重要转化研究，并可能激励其他常见复杂疾病的类似方法。

DESCRIPTION (provided by applicant): Hypertension and its sequelae constitute a major public-health burden and, therefore-, identification of the causal variants for hypertension could lead to the development of novel interventions to control or treat the adverse outcomes. Although Genome-Wide Association Studies (GWAS) have successfully identified 29 common variants for hypertension, their effects collectively explain less than 2.5% of blood pressure (BP) variance, with most of the heritability still missing. We propose a comprehensive study to identify rare and low frequency variants with supposedly larger effects for hypertension and high BP in highly enriched Taiwan Chinese hypertensive families using whole exome sequencing and state-of-the-art statistical methods. The SAPPHIRe Network in the Family Blood Pressure Program (FBPP) recruited Taiwan families with multiple hypertensive sibs. Thus, by the very design of the study, the family sample is highly enriched with hypertension and BP segregating variants. We show that this type of recruitment and further selection of a subset of the families with strong linkage evidence vastly enriches rare and low frequency variants for hypertension/BP by several fold as compared to the general population. Therefore, we propose to carry out exome sequencing in 150 highly enriched Taiwan sib-pairs (300 subjects) and 300 unrelated controls from Taiwan, and genotype the top 6,000 SNPs in all SAPPHIRe families (N=1,200) and 1,200 unrelated matched controls. Finally, the 50 variants most associated with hypertension/BP will then be replicated in large multi- ethnic cohorts, including Chinese and U.S. populations, with nearly 45,000 subjects. This study can potentially explain a large proportion of the missing heritability, which could then lead to important translational research o considerable public health significance. Therefore, the potential impact is very high. PUBLIC HEALTH RELEVANCE: The primary goal of the proposed research is to identify rare and low frequency variants that have large effects on blood pressure and hypertension by carrying out exome sequencing in 150 highly enriched Taiwan Chinese sib-pairs (300 subjects) and 300 unrelated controls, then to validate the top 6,000 SNPs in larger samples, and finally replicate the top 50 SNPs in nearly 45,000 multi-ethnic subjects. Any success with hypertension can lead to important translational research of considerable public health significance and will likely motivate similar approaches for other common complex diseases.