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.

抽象的 慢性肾病是一种进行性、异质性的疾病，影响 10% 的人 在世界范围内，它是过早心血管疾病和死亡的原因。人们对其机制知之甚少 导致其发展和倾向。尽管有强有力的证据表明血统在慢性病中发挥着作用 肾脏疾病的易感性，很少有研究利用血统来发现基因。西班牙裔是一个 未被充分研究的少数群体，由许多重叠的祖先群体（美洲印第安人、西方人）组成 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，并且 它们相应的罕见和常见的遗传变异，解释了慢性肾病的易感性较高 西班牙裔的疾病。我们将使用新颖的混合物作图方法来绘制基因组片段和 从具有较高疾病变异频率的祖先群体遗传的变异（目标 1），其次是 对特定血统群体（西班牙裔、美洲印第安人、 欧洲和西非血统）（目标 2）。我们将利用来自大量西班牙裔人口的数据 社区健康研究/拉丁裔基因发现研究，并建议使用 基因分型和靶向测序相结合。深入了解已确定的职能角色 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实验的变体 基因靶向研究（目标 3）。该提案利用血统来识别西班牙裔肾脏特征的基因座， 并独特地补充大型正在进行的全基因组关联方法。我们的结果将提供线索 疾病风险方面的种族/民族差异，并提高对导致疾病的生物学途径的了解 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众健康。

项目成果

Genetic Testing in Clinical Settings.

临床环境中的基因检测。

• 发表时间: 2018-10
• 作者: Franceschini, Nora;Frick, Amber;Kopp, Jeffrey B
• 通讯作者: Kopp, Jeffrey B

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

西班牙裔/拉丁裔人群的多基因风险评分和肾脏特征：西班牙裔社区健康研究/拉丁裔研究。

• 发表时间: 2023-04-13
• 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

Genetics in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

慢性肾脏病的遗传学：肾脏病：改善全球成果（KDIGO）争议会议的结论。

• DOI: 10.1016/j.kint.2022.03.019
• 发表时间: 2022-06
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Koettgen, Anna;Cornec-Le Gall, Emilie;Halbritter, Jan;Kiryluk, Krzysztof;Mallett, Andrew J.;Parekh, Rulan S.;Rasouly, Hila Milo;Sampson, Matthew G.;Tin, Adrienne;Antignac, Corinne;Ars, Elisabet;Bergmann, Carsten;Bleyer, Anthony J.;Bockenhauer, Detlef;Devuyst, Olivier;Florez, Jose C.;Fowler, Kevin J.;Franceschini, Nora;Fukagawa, Masafumi;Gale, Daniel P.;Gbadegesin, Rasheed A.;Goldstein, David B.;Grams, Morgan E.;Greka, Anna;Gross, Oliver;Guay-Woodford, Lisa M.;Harris, Peter C.;Hoefele, Julia;Hung, Adriana M.;Knoers, Nine V. A. M.;Kopp, Jeffrey B.;Kretzler, Matthias;Lanktree, Matthew B.;Lipska-Zietkiewicz, Beata S.;Nicholls, Kathleen;Nozu, Kandai;Ojo, Akinlolu;Parsa, Afshin;Pattaro, Cristian;Pei, York;Pollak, Martin R.;Rhee, Eugene P.;Sanna-Cherchi, Simone;Savige, Judy;Sayer, John A.;Scolari, Francesco;Sedor, John R.;Sim, Xueling;Somlo, Stefan;Susztak, Katalin;Tayo, Bamidele O.;Torra, Roser;van Eerde, Albertien M.;Weinstock, Andre;Winkler, Cheryl A.;Wuttke, Matthias;Zhang, Hong;King, Jennifer M.;Cheung, Michael;Jadoul, Michel;Winkelmayer, Wolfgang C.;Gharavi, Ali G.
• 通讯作者: Gharavi, Ali G.

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

3604 GWAS 的综合分析揭示了多种新型细胞类型特异性调控关联。

• 发表时间: 2022-01-07
• 影响因子: 12.3
• 作者: Breeze, Charles E;Haugen, Eric;Reynolds, Ale;Teschendorff, Andrew;van Dongen, Jenny;Lan, Qing;Rothman, Nathaniel;Bourque, Guillaume;Dunham, Ian;Beck, Stephan;Stamatoyannopoulos, John;Franceschini, Nora;Berndt, Sonja I
• 通讯作者: Berndt, Sonja I

The missing diversity in human epigenomic studies.

人类表观基因组研究中缺失的多样性。

• 发表时间: 2022-06
• 影响因子: 30.8
• 作者: Breeze, Charles E;Beck, Stephan;Berndt, Sonja I;Franceschini, Nora
• 通讯作者: Franceschini, Nora