Genetic Basis of Cryptorchidism

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性基因组变异，这表明更常见的等位基因变异增加了遗传易感性。因此，我们提出了一项全基因组关联研究，该研究将使用协作方法来优化确定非综合征性隐睾易感位点的可能性。我们将利用4个主要机构以前和正在收集的样本，其中一个机构拥有完善的基因分型设施和极其庞大的健康儿童基因型数据库，一个新一代基因分型平台，可以查询单核苷酸多态性（SNPs）和拷贝数变异（CNV）区域，并正在进行动物模型中隐睾遗传基础的研究，以测试候选基因。我们将使用两阶段的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）中寻找全基因组显著位点。在第二阶段，我们将在两个独立的组（病例对照和三组）中对全基因组范围内显著的snp / cnv进行基因分型，以便进行复制，并在这些队列中对提示位点上的snp / cnv进行基因分型，以提高检测全基因组意义的能力。我们将研究候选基因在大鼠靶组织中的重要表达位点以及功能snp与隐睾症的关联。这一新的研究者发起的建议将利用现有的、互补的临床和动物模型资源，提供一种新的方法来识别与隐睾风险有关的基因组位点，并为未来研究隐睾的预防、诊断和预后提供基础。

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.