Leveraging ancestry to map kidney loci

利用祖先来绘制肾脏位点图

• 批准号: 10183320
• 负责人: Nora Franceschini
• 金额: $ 69.54万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-24 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183320
• 关键词: APOL1 gene; Address; Admixture; Affect; Africa; African; African American; Albumins; Albuminuria; Alleles; American; American Indians; Amerindian; Biological; Biological Models; Candidate Disease Gene; Cardiovascular Diseases; Cessation of life; Chronic Kidney Failure; Complement; Complex; Country; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Disease susceptibility; End stage renal failure; European; Excretory function; Experimental Models; Focal Segmental Glomerulosclerosis; Frequencies; Gene Frequency; Gene Targeting; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic study; Genomic Segment; Genomics; Genotype; Glomerular Filtration Rate; HIV; Heterogeneity; High Prevalence; Hispanic Americans; Hispanic Community Health Study/Study of Latinos; Hispanics; In Vitro; Individual; Inherited; Kidney; Latino; Maps; Meta-Analysis; Metabolic; Methods; Minority Groups; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Orthologous Gene; Participant; Pathway interactions; Phenotype; Population; Population Genetics; Predisposition; Public Health; Renal function; Research; Risk; Role; SNP genotyping; Single Nucleotide Polymorphism; Subgroup; Testing; Transgenic Organisms; Validation; Variant; admixture mapping; ancestry analysis; base; biobank; causal variant; clinical biomarkers; cohort; diabetic; differential expression; disease phenotype; disorder risk; ethnic disparity; experimental study; gene discovery; genetic variant; genome wide association study; improved; insight; mouse model; multi-ethnic; novel; personalized medicine; population based; premature; racial and ethnic; racial and ethnic disparities; rare variant; study population; targeted sequencing; trait; urinary

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.

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，并改善公共卫生。

项目成果

Integrative analysis of 3604 GWAS reveals multiple novel cell type-specific regulatory associations.

• DOI: 10.1186/s13059-021-02560-3
• 发表时间: 2022-01-07
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Breeze CE;Haugen E;Reynolds A;Teschendorff A;van Dongen J;Lan Q;Rothman N;Bourque G;Dunham I;Beck S;Stamatoyannopoulos J;Franceschini N;Berndt SI
• 通讯作者: Berndt SI

FORGEdb: a tool for identifying candidate functional variants and uncovering target genes and mechanisms for complex diseases.

• DOI: 10.1186/s13059-023-03126-1
• 发表时间: 2024-01-02
• 期刊: Genome biology
• 影响因子: 12.3

Mendelian randomization analyses suggest a causal role for circulating GIP and IL-1RA levels in homeostatic model assessment-derived measures of β-cell function and insulin sensitivity in Africans without type 2 diabetes.

孟德尔随机分析表明，在没有2型糖尿病的非洲人中，在稳态模型评估衍生的β细胞功能和胰岛素敏感性的测量中，循环GIP和IL-1RA水平的因果作用。

• DOI: 10.1186/s13073-023-01263-7
• 发表时间: 2023-12-04
• 期刊: Genome medicine
• 影响因子: 12.3

Polygenic risk scores and kidney traits in the Hispanic/Latino population: The Hispanic Community Health Study/Study of Latinos.

西班牙裔/拉丁裔人口中的多基因风险评分和肾脏特征：西班牙裔社区健康研究/拉丁美洲人研究。

• DOI: 10.1016/j.xhgg.2023.100177
• 发表时间: 2023-04-13
• 期刊: HUMAN GENETICS AND GENOMICS ADVANCES
• 作者: Zhou, Laura Y.;Sofer, Tamar;Horimoto, Andrea R. V. R.;Talavera, Gregory A.;Lash, James P.;Cai, Jianwen;Franceschini, Nora
• 通讯作者: Franceschini, Nora

Admixture mapping in the Hispanic Community Health Study/Study of Latinos reveals regions of genetic associations with blood pressure traits.

• DOI: 10.1371/journal.pone.0188400
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sofer T;Baier LJ;Browning SR;Thornton TA;Talavera GA;Wassertheil-Smoller S;Daviglus ML;Hanson R;Kobes S;Cooper RS;Cai J;Levy D;Reiner AP;Franceschini N
• 通讯作者: Franceschini N