Genetic Basis of Cryptorchidism

隐睾的遗传基础

• 批准号: 8101957
• 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
• 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/8101957
• 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 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 Studies; 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; human data; in vitro Assay; insight; mRNA Expression; male; malformation; novel strategies; outcome forecast; programs; public health relevance; relaxin receptor; sample collection

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）：隐睾是一种常见的先天性异常，有证据表明多位点遗传贡献。在绝大多数情况下，对睾丸下降重要的候选基因的分析未能检测到功能基因组变异，这表明更常见的等位基因变异对遗传易感性有附加作用。因此，我们提出了一项全基因组关联研究，该研究将使用协作方法来优化定义非综合征性隐睾易感位点的可能性。我们将利用 4 个主要机构之前和正在进行的样本收集，其中一个拥有完善的基因分型设施和来自健康儿童的极其庞大的基因型数据库，新一代基因分型平台，可询问单核苷酸多态性 (SNP) 和拷贝数变异 (CNV) 区域，以及正在进行的动物模型中隐睾遗传基础的研究，以测试基因 候选人。我们将采用两阶段方法完成全基因组关联（GWA）研究。在第一阶段，我们将在大型病例对照队列（1:3 比例）中寻找全基因组的重要位点。在第二阶段，我们将对两个独立组（病例对照和三组）中的全基因组显着 SNP/CNV 进行基因分型，以进行复制，并在这些队列中的提示性位点上对 SNP/CNV 进行基因分型，以提高检测全基因组显着性的能力。我们将研究重要位点的候选基因在大鼠靶组织中的表达以及功能性 SNP 与隐睾的关联。这项由研究者发起的新提案将利用现有的、互补的临床和动物模型资源，提供一种新的方法来识别导致隐睾风险的基因组位点，并为未来的隐睾预防、诊断和预后研究提供基础。 公共卫生相关性：隐睾是最常见的出生缺陷之一，影响 1-4% 的男童。其原因尚不清楚，但双胞胎和家庭研究表明存在遗传因素。该项目拟通过开展全基因组关联研究来识别影响隐睾易感性的遗传变异，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。