• PMID: 26209787
• Gene Name: RXFP2
• Condition: Nonsyndromic cryptorchidism
• Association: Genes linked to human syndromic cryptorchidism, including hypogonadotropichypogonadism, and to hormone-responsive and/or differentially expressed genes in normal and cryptorchid rat gubernaculum, were also significantly overrepresented. No tested marker s
• Population size: 3562
• Population details: 3562 (844 boys with nonsyndromic cryptorchidism, 2718 control subjects without syndromes or genital anomalies)
• Sex: Male
• Infertility type: Male infertility
• Associated genes: INSL3, RXFP2
• Other associated phenotypes: Nonsyndromic cryptorchidism

Pathway analysis supports association of nonsyndromic cryptorchidism with genetic loci linked to cytoskeleton-dependent functions

Barthold JS, Wang Y, Kolon TF, Kollin C, Nordenskjöld A, Olivant Fisher A, Figueroa TE, BaniHani AH, Hagerty JA, Gonzaléz R, Noh PH, Chiavacci RM, Harden KR, Abrams DJ, Kim CE, Li J, Hakonarson H, Devoto M.

STUDY QUESTION: What are the genetic loci that increase susceptibility to nonsyndromic cryptorchidism, or undescended testis? SUMMARY ANSWER: A genome-wide association study (GWAS) suggests that susceptibility to cryptorchidism is heterogeneous, with a subset of suggestive signals linked to cytoskeleton-dependent functions and syndromic forms of the disease. WHAT IS KNOWN ALREADY: Population studies suggest moderate genetic risk of cryptorchidism and possible maternal and environmental contributions to risk. Previous candidate gene analyses have failed to identify a major associated locus, although variants in insulin-like 3 (INSL3), relaxin/insulin-like family peptide receptor 2 (RXFP2) and other hormonal pathway genes may increase risk in a small percentage of patients. STUDY DESIGN, SIZE, DURATION: This is a case-control GWAS of 844 boys with nonsyndromic cryptorchidism and 2718 control subjects without syndromes or genital anomalies, all of European ancestry. PARTICIPANTS/MATERIALS, SETTING, METHODS: All boys with cryptorchidism were diagnosed and treated by a pediatric specialist. In the discovery phase, DNA was extracted from tissue or blood samples and genotyping performed using the Illumina HumanHap550 and Human610-Quad (Group 1) or OmniExpress (Group 2) platform. We imputed genotypes genome-wide, and combined single marker association results in meta-analyses for all cases and for secondary subphenotype analyses based on testis position, laterality and age, and defined genome-wide significance as P = 7 × 10(-9) to correct for multiple testing. Selected markers were genotyped in an independent replication group of European cases (n = 298) and controls (n = 324). We used several bioinformatics tools to analyze top (P < 10(-5)) and suggestive (P < 10(-3)) signals for significant enrichment of signaling pathways, cellular functions and custom gene lists after multiple testing correction. MAIN RESULTS AND THE ROLE OF CHANCE: In the full analysis, we identified 20 top loci, none reaching genome-wide significance, but one passing this threshold in a subphenotype analysis of proximal testis position (rs55867206, near SH3PXD2B, odds ratio = 2.2 (95% confidence interval 1.7, 2.9), P = 2 × 10(-9)). An additional 127 top loci emerged in at least one secondary analysis, particularly of more severe phenotypes. Cytoskeleton-dependent molecular and cellular functions were prevalent in pathway analysis of suggestive signals, and may implicate loci encoding cytoskeletal proteins that participate in androgen receptor signaling. Genes linked to human syndromic cryptorchidism, including hypogonadotropic hypogonadism, and to hormone-responsive and/or differentially expressed genes in normal and cryptorchid rat gubernaculum, were also significantly overrepresented. No tested marker showed significant replication in an independent population. The results suggest heterogeneous, multilocus and potentially multifactorial susceptibility to nonsyndromic cryptorchidism. LIMITATIONS, REASONS FOR CAUTION: The present study failed to identify genome-wide significant markers associated with cryptorchidism that could be replicated in an independent population, so further studies are required to define true positive signals among suggestive loci. WIDER IMPLICATIONS OF THE FINDINGS: As the only GWAS to date of nonsyndromic cryptorchidism, these data will provide a basis for future efforts to understand genetic susceptibility to this common reproductive anomaly and the potential for additive risk from environmental exposures. STUDY FUNDING/COMPETING INTERESTS: This work was supported by R01HD060769 (the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD)), P20RR20173 (the National Center for Research Resources (NCRR), currently P20GM103464 from the National Institute of General Medical Sciences (NIGMS)), an Institute Development Fund to the Center for Applied Genomics at The Children's Hospital of Philadelphia, and Nemours Biomedical Research. The authors have no competing interests to declare. CI - © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. FAU - Barthold, Julia Spencer AU - Barthold JS AD - Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA Division of Urology, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA jbarthol@nemours.org. FAU - Wang, Yanping AU - Wang Y AD - Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA. FAU - Kolon, Thomas F AU - Kolon TF AD - Division of Urology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. FAU - Kollin, Claude AU - Kollin C AD - Department of Women's and Children's Health, Karolinska Institutet, SE-171 76 Stockholm, Sweden. FAU - Nordenskjöld, Agneta AU - Nordenskjöld A AD - Department of Women's and Children's Health, Karolinska Institutet, SE-171 76 Stockholm, Sweden. FAU - Olivant Fisher, Alicia AU - Olivant Fisher A AD - Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA. FAU - Figueroa, T Ernesto AU - Figueroa TE AD - Division of Urology, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA. FAU - BaniHani, Ahmad H AU - BaniHani AH AD - Division of Urology, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA. FAU - Hagerty, Jennifer A AU - Hagerty JA AD - Division of Urology, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA. FAU - Gonzaléz, Ricardo AU - Gonzaléz R AD - Division of Urology, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA Present address: Auf der Bult Kinder- und Jugendkrankenhaus, Hannover, Germany. FAU - Noh, Paul H AU - Noh PH AD - Division of Urology, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA Present address: Division of Pediatric Urology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. FAU - Chiavacci, Rosetta M AU - Chiavacci RM AD - Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. FAU - Harden, Kisha R AU - Harden KR AD - Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. FAU - Abrams, Debra J AU - Abrams DJ AD - Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. FAU - Kim, Cecilia E AU - Kim CE AD - Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. FAU - Li, Jin AU - Li J AD - Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. FAU - Hakonarson, Hakon AU - Hakonarson H AD - Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.