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，有证据表明存在多位点遗传贡献。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性基因组变异，这表明更常见的等位基因变异可增加遗传易感性。因此，我们提出了一个全基因组关联研究，将使用一种合作的方法来优化定义非综合征型隐睾症易感基因座的可能性。我们将利用4个主要机构以前和正在进行的样本收集，其中一个机构拥有完善的基因分型设施和非常大的健康儿童基因型数据库，新一代基因分型平台，可同时检测单核苷酸多态性（SNP）和拷贝数变异（CNV）区域以及正在进行的隐睾症基因基础的动物模型研究，以测试候选基因。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，我们将在一个大型病例对照队列（1：3比例）中寻找全基因组显著位点。在第2阶段，我们将在两个独立的组（病例对照组和三人组）中对全基因组显著的SNP/CNV进行基因分型，以进行复制，并在这些队列中对提示性位点的SNP/CNV进行基因分型，以提高检测全基因组显著性的能力。我们将研究在大鼠靶组织中表达的重要位点的候选基因，以及功能性SNP与隐睾症的关联。这项新的研究者发起的提案将利用现有的、互补的临床和动物模型资源，提供一种新的方法来鉴定有助于隐睾风险的基因组位点，并为未来隐睾预防、诊断和预后的研究提供基础。 公共卫生相关性：隐睾症是最常见的出生缺陷之一，影响1-4%的男孩。其原因尚不清楚，但从双胞胎和家庭研究中发现了遗传因素。该项目建议通过进行全基因组关联研究来确定影响隐睾易感性的遗传变异，该研究将在4个主要机构的样本中寻找DNA结构和方向的变异。