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%的个体 这是世界范围内的一种疾病，也是过早心血管疾病和死亡的原因。人们对这些机制知之甚少 导致其发展和倾向。尽管有强有力的证据表明祖先在慢性疾病中的作用， 肾脏疾病的易感性，很少有研究利用祖先的基因发现。西班牙裔是一个 由许多重叠的祖先群体组成的未被充分研究的少数民族（美洲印第安人，西 非洲、欧洲）。西班牙裔人蛋白尿增加和终末期肾病的患病率很高， 这与他们的美洲印第安血统有关。我们建议确定祖先特异性基因座， 它们相应的罕见和常见遗传变异，解释了慢性肾脏病的易感性较高。 西班牙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， 从祖先群体遗传的变异，具有较高的疾病变异频率（目标1），其次是 精细映射和验证祖先特定队列（西班牙裔，美洲印第安人， 欧洲和西非血统）（目标2）。我们将利用大量基于人口的西班牙裔美国人的数据， 社区健康研究/拉丁美洲人的基因发现研究，并建议使用 基因分型和靶向测序的组合。深入了解已确定的 基因，我们将优先考虑使用体外和小鼠模型系统进行转基因和 基因靶向研究（Aim 3）。这项提案利用祖先来确定西班牙裔人肾脏性状的基因座， 并且独特地补充了正在进行的大的全基因组关联方法。我们的结果将提供线索 疾病风险的种族/民族差异，并提高对导致疾病的生物学途径的理解， 慢性肾病最终，这项研究可以为个性化医疗提供信息，并改善公共卫生。

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.