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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Genetics of Health and Disease Study Section (GHD)
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Taymans, Susan
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Alfred I. Du Pont Hosp for Children
United States
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Barthold, Julia S; Ivell, Richard (2018) Perspective: A Neuro-Hormonal Systems Approach to Understanding the Complexity of Cryptorchidism Susceptibility. Front Endocrinol (Lausanne) 9:401
Barthold, Julia Spencer; Wintner, Anton; Hagerty, Jennifer A et al. (2018) Cryptorchidism in Boys With Cerebral Palsy Is Associated With the Severity of Disease and With Co-Occurrence of Other Congenital Anomalies. Front Endocrinol (Lausanne) 9:151
Wang, Yanping; Gray, Dione R; Robbins, Alan K et al. (2018) Subphenotype meta-analysis of testicular cancer genome-wide association study data suggests a role for RBFOX family genes in cryptorchidism susceptibility. Hum Reprod 33:967-977
Wang, Yanping; Li, Jin; Kolon, Thomas F et al. (2016) Genomic copy number variation association study in Caucasian patients with nonsyndromic cryptorchidism. BMC Urol 16:62
Barthold, Julia Spencer; Pugarelli, Joan; MacDonald, Madolyn L et al. (2016) Polygenic inheritance of cryptorchidism susceptibility in the LE/orl rat. Mol Hum Reprod 22:18-34
Robbins, Alan K; Mateson, Abigail B; Khandha, Ashutosh et al. (2016) Fetal Rat Gubernaculum Mesenchymal Cells Adopt Myogenic and Myofibroblast-Like Phenotypes. J Urol 196:270-8
Barthold, Julia S; Wang, Yanping; Kolon, Thomas F et al. (2015) Phenotype specific association of the TGFBR3 locus with nonsyndromic cryptorchidism. J Urol 193:1637-45
Barthold, Julia Spencer; Wang, Yanping; Kolon, Thomas F et al. (2015) Pathway analysis supports association of nonsyndromic cryptorchidism with genetic loci linked to cytoskeleton-dependent functions. Hum Reprod 30:2439-51
Barthold, Julia S; Robbins, Alan; Wang, Yanping et al. (2014) Cryptorchidism in the orl rat is associated with muscle patterning defects in the fetal gubernaculum and altered hormonal signaling. Biol Reprod 91:41
Barthold, Julia S; Wang, Yanping; Robbins, Alan et al. (2013) Transcriptome analysis of the dihydrotestosterone-exposed fetal rat gubernaculum identifies common androgen and insulin-like 3 targets. Biol Reprod 89:143

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