Leveraging ancestry to map kidney loci

摘要 慢性肾脏疾病是一种进行性和异质性的疾病，影响10%的人。 在世界范围内，也是导致过早心血管疾病和死亡的原因之一。人们对这种机制知之甚少。 导致了它的发展和易感性。尽管有强有力的证据表明祖先在慢性阻塞性肺疾病中的作用 关于肾脏疾病的易感性，很少有研究利用祖先来发现基因。拉美裔是一种 由许多重叠的祖先群体(美洲印第安人、西部人)组成的未被研究的少数民族群体 非洲、欧洲)。拉美裔人蛋白尿增加和终末期肾脏疾病的患病率很高， 这与他们的美洲印第安人血统有关。我们建议识别特定于祖先的基因座，并且 他们相应的罕见和常见的基因变异，解释了慢性肾脏的更高易感性 拉美裔美国人的疾病。我们将使用新的混合作图方法来绘制基因组片段和 从疾病变异频率较高的祖先群体继承的变异(目标1)，其次是 对特定祖先的队列(西班牙裔、美国印第安人、 欧洲和西非的祖先)(目标2)。我们将利用以大量人口为基础的西班牙裔美国人的数据 社区健康研究/拉丁裔基因发现研究，并建议使用A 基因分型和靶向测序相结合。深入了解已确定的功能角色 基因，我们将优先使用体外和小鼠模型系统进行转基因和 基因打靶研究(目标3)。这项建议利用血统来确定拉美裔人肾脏特征的基因座， 并独一无二地补充了正在进行的大规模全基因组关联方法。我们的结果将提供线索 在疾病风险方面的种族/民族差异，并提高对导致 慢性肾脏疾病。最终，这项研究可以为个性化医疗提供信息，并改善公共健康。

ABSTRACT Chronic kidney disease is a progressive and heterogeneous condition that affects 10% of individuals worldwide, and a cause of premature cardiovascular disease and death. Little is known about the mechanisms leading to its development and predisposition. Despite the strong evidence for a role of ancestry in chronic kidney disease susceptibility, few studies have leveraged ancestry for gene discovery. Hispanics are an understudied minority group that is comprised of many overlapping ancestral groups (Amerindian, West African, European). Hispanics have a high prevalence of increased albuminuria and end-stage renal disease, which has been associated with their Amerindian ancestry. We propose to identify ancestry-specific loci, and their corresponding rare and common genetic variants, that explain the higher susceptibility for chronic kidney disease in Hispanics. We will use novel admixture mapping approaches to map genomic segments and variants inherited from the ancestral population with the higher disease variant frequency (Aim 1), followed by fine-mapping and validation of associations in ancestry-specific cohorts (Hispanics, American Indians, European and West Africa ancestries) (Aim 2). We will leverage data from the large population-based Hispanic Community Health Study/Study of Latinos for gene discovery, and propose to fine-map Amerindian loci using a combination of genotyping and targeted sequencing. To gain insights into the functional roles of identified genes, we will prioritize variants for experiments using in vitro and mouse model systems for transgenic and gene targeting studies (Aim 3). This proposal leverages ancestry to identify loci for kidney traits in Hispanics, and uniquely complement large ongoing genome wide association approaches. Our results will provide clues to racial/ethnic disparities in disease risk, and improve understanding of the biological pathways leading to chronic kidney disease. Ultimately this research could inform personalized medicine and improve public health.