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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD060769-04
Application #
8485409
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Taymans, Susan
Project Start
2010-06-27
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$362,754
Indirect Cost
$47,554
Name
Alfred I. Du Pont Hosp for Children
Department
Type
DUNS #
038004941
City
Wilmington
State
DE
Country
United States
Zip Code
19803