Genetics of human renal hypodysplasia

人类肾发育不良的遗传学

• 批准号: 10241548
• 负责人: ALI G GHARAVI
• 金额: $ 59.34万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241548
• 关键词: 16p13.3; 17q12; 1q21; 22q11.2; Adult; Anxiety; Biological; CRKL gene; Childhood; Clinical; Code; Complication; Congenital Abnormality; Congenital Heart Defects; Copy Number Polymorphism; Data; Development; Diagnosis; Diagnostic; Disease; Early Intervention; End stage renal failure; Ensure; Gene Frequency; Genes; Genetic; Genome; Genomics; Hand; Heart Abnormalities; Heritability; Human Genetics; Impairment; Inherited; Intelligence; Investigation; Kidney; Kidney Diseases; Kidney Failure; Lower urinary tract; Measures; Mutation; Neurocognition; Organ; Outcome; Pathogenicity; Pathway interactions; Patient Care; Patients; Penetrance; Phenotype; Research Personnel; Risk; Sampling; Severity of illness; Single Nucleotide Polymorphism; Suggestion; Susceptibility Gene; Syndrome; Testing; United States National Institutes of Health; Untranslated RNA; Urinary tract; Uterus; Variant; Work; case control; clinical care; clinical phenotype; cohort; comorbidity; database of Genotypes and Phenotypes; de novo mutation; depressive symptoms; developmental disease; disorder risk; executive function; exome; exome sequencing; fetal; genetic approach; genetic variant; genome sequencing; genome wide association study; insertion/deletion mutation; kidney malformation; large datasets; loss of function mutation; malformation; novel; pediatric patients; pleiotropism; polygenic risk score; prognostic tool; programs; rare variant; recruit; trait; whole genome

Renal hypodysplasia (RHD) is a congenital malformation of the kidney often associated with additional malformations and clinical complications. Overall, kidney and urinary tract malformations main complication is end-stage kidney failure (ESRD), and they account for up to 50% of pediatric and 7% of adult ESRD worldwide. The biological basis of RHD is poorly understood. Currently rare variants in known genes (single nucleotide variants and small insertion deletion variants, or SNVs) and rare copy-number variants (CNVs) only explain the cause of 10-20% of RHD, limiting the development of optimal diagnostic and prognostic tools. Interestingly, our preliminary data suggest that common variants are significantly associated with kidney and urinary tract malformations, pointing to another mechanism to resolve the missing heritability of RHD. The central hypothesis of this application is that comprehensive genetic approaches can advance our understanding of the biological basis of RHD. The rationale underlying the application is that all types of genetic variants (common and rare, SNVs and CNVs, de novo and inherited) can cause RHD, and that some of the comorbidities associated with RHD can help identify novel genes associated with syndromic RHD. To ensure a comprehensive analysis, we will pursue three aims: 1) As de novo variants are known to be an important mechanism for developmental disorders, we will analyze the burden of all types of de novo variants (SNVs, CNVs and non-coding variants). 2) As both inherited and de novo mutations contribute to RHD and have pleiotropic effects on the development of other organs, we will also utilize case-control approach. To increase our statistical power, we will then combine the results from the case-control analysis with the results from the de novo analysis, and take advantage of the large publicly available sequenced cohorts of patients with RHD comorbidities to perform a combined case-control analysis. 3) We will test whether common variants can increase the risk for RHD by performing genome-wide association analysis on a large set of cases and controls, and calculating a polygenic risk score to predict RHD (RHD- PRS). We will then analyze the association between the RHD-PRS to its comorbidities, and examine whether the RHD-PRS can modify the effect of rare pathogenic variants. Taken together, this application will investigate variation across a range of allele frequencies, to better understand their contribution to pleiotropy, penetrance and clinical severity of disease. The project benefits from the researchers expertise in Human Genetic, large cohorts of RHD cases, and recent support from the NIH X01 program for whole genome sequencing.

肾发育不全（RHD）是一种先天性肾脏畸形，通常伴有 其他畸形和临床并发症。总体而言，肾脏和泌尿道 畸形的主要并发症是终末期肾衰竭（ESRD），它们占 全球50%的儿童和7%的成人ESRD。风心病的生物学基础较差 明白目前已知基因中罕见的变异（单核苷酸变异和小 插入缺失变异（SNVs）和罕见拷贝数变异（CNVs）仅解释了 这是10-20% RHD的原因，限制了最佳诊断和预后工具的发展。 有趣的是，我们的初步数据表明，常见的变异显着相关 肾脏和尿路畸形，指出另一种机制，以解决 RHD的遗传性缺失。本申请的中心假设是， 遗传学方法可以促进我们对风湿性心脏病生物学基础的理解。的 申请的基本原理是所有类型的遗传变异（常见和罕见，SNV 和CNV，新生和遗传）可导致RHD，并且一些合并症 与风湿性心脏病相关的基因可以帮助鉴定与综合征型风湿性心脏病相关的新基因。确保 一个全面的分析，我们将追求三个目标：1）作为新生变种已知是 发育障碍的一个重要机制，我们将分析所有类型的负担 的从头变异（SNV，CNV和非编码变异）。2)既继承又发展 新生突变导致RHD，并对其他疾病的发展具有多效性作用。 器官，我们也将利用病例对照的方法。为了提高我们的统计能力，我们将 联合收割机将病例对照分析的结果与从头分析的结果结合起来， 并利用大量公开的RHD患者的测序队列， 合并症进行联合病例对照分析。3)我们将测试是否常见 变异可以通过对RHD患者进行全基因组关联分析， 大量的病例和对照，并计算多基因风险评分来预测RHD（RHD- PRS）。然后，我们将分析RHD-PRS与其合并症之间的关联， 检查RHD-PRS是否可以改变罕见致病性变体的效果。采取 总之，本申请将研究等位基因频率范围内的变化，以更好地 了解它们对多效性、特异性和疾病临床严重程度的影响。的 该项目受益于研究人员在人类遗传学方面的专业知识，大量的RHD病例， 以及最近来自NIH X 01全基因组测序计划的支持。