Genetic Basis of Cryptorchidism

隐睾的遗传基础

基本信息

批准号：
7782991
负责人：
Julia Spencer Barthold
金额：
$ 54.81万
依托单位：
ALFRED I. DU PONT HOSP FOR CHILDREN
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-27 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7782991
关键词：
Address Affect Androgens Animal Model Animals Area Candidate Disease Gene Child Clinical Complex Congenital Abnormality Copy Number Polymorphism Cryptorchidism DNA DNA Structure Databases Development Diagnosis Disease Environmental Exposure Etiology European Family Family Study Fetal Tissues Future Gene Expression Regulation Gene Proteins Generations Genes Genetic Genetic Predisposition to Disease Genetic Variation Genomics Genotype Goals Housing Human Hybrids In Situ Hybridization Individual Inherited Institution Insulin Modeling Molecular Pathway interactions Pattern Pediatric Hospitals Peptide Receptor Phenotype Philadelphia Polygenic Traits Predisposition Prevention Proteins RNA Splicing Rat Strains Rattus Regulation Research Personnel Resources Risk Role Sampling Single Nucleotide Polymorphism Specificity Staging Technology Testicular Hormones Testing Testis Tissues Twin Multiple Birth Variant animal data base case control cohort density fetal functional genomics genetic linkage analysis genetic pedigree genetic variant genome wide association study genome-wide hormone sensitivity in vitro Assay insight mRNA Expression male malformation novel strategies outcome forecast programs public health relevance relaxin receptor sample collection

项目摘要

DESCRIPTION (provided by applicant): Cryptorchidism is a common congenital anomaly with evidence for multilocus genetic contribution. Analysis of candidate genes important for testicular descent has failed to detect functional genomic variants in the vast majority of cases, suggesting that more common allelic variants additively contribute to genetic susceptibility. Consequently, we propose a genome-wide association study that will use a collaborative approach to optimize the likelihood of defining susceptibility loci for non- syndromic cryptorchidism. We will capitalize upon previous and ongoing sample collection at 4 major institutions, one of which houses a well-established genotyping facility and extremely large database of genotypes from healthy children, a newer generation genotyping platform that interrogates both single nucleotide polymorphisms (SNPs) and areas of copy number variation (CNV) and ongoing studies of the genetic basis of cryptorchidism in an animal model for testing of gene candidates. We will complete a genome-wide association (GWA) study using a two-stage approach. In Stage 1, we will search for genome-wide significant loci in a large case-control cohort (1:3 ratio). In Stage 2, we will genotype genome-wide significant SNPs/CNVs in two independent groups (case-control and trios) for replication, and SNPs/CNVs at suggestive loci in these cohorts for increased power to detect genome-wide significance. We will study candidate genes at significant loci for expression in rat target tissues and for association of functional SNPs with cryptorchidism. This new investigator- initiated proposal will capitalize on existing, complementary clinical and animal model resources, provide a novel approach to identifying genomic loci that contribute to the risk of cryptorchidism and provide a basis for future studies of cryptorchidism prevention, diagnosis and prognosis. PUBLIC HEALTH RELEVANCE: Cryptorchidism is one of the most common birth defects, affecting 1-4% of male children. The cause remains unknown but a hereditary component has been implicated from twin and family studies. This project proposes to identify genetic variants that influence susceptibility to cryptorchidism by conducting a genome-wide association study that will look for variations in DNA structure and orientation in samples from 4 major institutions.

描述（由申请人提供）：隐齿术是一种常见的先天性异常，具有多焦点遗传贡献的证据。对睾丸下降重要的候选基因的分析未能检测到绝大多数病例中的功能基因组变异，这表明更常见的等位基因变体累积地有助于遗传易感性。因此，我们提出了一项全基因组关联研究，该研究将使用一种协作方法来优化定义非综合症隐式术的易感基因座的可能性。 We will capitalize upon previous and ongoing sample collection at 4 major institutions, one of which houses a well-established genotyping facility and extremely large database of genotypes from healthy children, a newer generation genotyping platform that interrogates both single nucleotide polymorphisms (SNPs) and areas of copy number variation (CNV) and ongoing studies of the genetic basis of cryptorchidism in an animal model for testing of gene候选人。我们将使用两阶段方法完成全基因组关联（GWA）研究。在第1阶段，我们将在大病例对照组中搜索全基因组显着的基因座（1：3比率）。在第2阶段中，我们将在两个独立组（病例对照和三个基因组）中进行基因组范围的明显SNP/CNV进行复制，并在这些同龄人群中有启发性的基因座的SNP/CNV，以增加能力以检测全基因组显着性。我们将研究重要基因座的候选基因在大鼠靶组织中表达以及功能性SNP与隐齿术的缔合。这项新的研究者提出的提案将利用现有的互补临床和动物模型资源，为识别基因组基因座提供了一种新颖的方法，该方法有助于加密治疗的风险，并为未来的预防隐式治疗，诊断和预后提供了基础。公共卫生相关性：密码轨道主义是最常见的先天缺陷之一，影响了1-4％的男性儿童。原因仍然未知，但是双胞胎和家庭研究与遗传成分有关。该项目建议通过进行全基因组关联研究来确定影响对隐式术敏感性的遗传变异，该研究将寻找来自4个主要机构的样本中DNA结构和方向的变化。