• PMID: 25390077
• Gene Name: TGFBR3
• Condition: Cryptorchidism
• Association: Associated
• Mutation: rs9661103, rs10782968, rs17576372, rs11165059, rs9661103, rs10782968
• Population size: 3562
• Population details: 3562 (844 cases and 2,718 controls)
• Sex: Male
• Infertility type: Male infertility
• Associated genes: GWAS

Phenotype specific association of the TGFBR3 locus with nonsyndromic cryptorchidism

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

PURPOSE: Based on a genome-wide association study of testicular dysgenesis syndrome showing a possible association with TGFBR3, we analyzed data from a larger, phenotypically restricted cryptorchidism population for potential replication of this signal. MATERIALS AND METHODS: We excluded samples based on strict quality control criteria, leaving 844 cases and 2,718 controls of European ancestry that were analyzed in 2 separate groups based on genotyping platform (ie Illumina® HumanHap550, version 1 or 3, or Human610-Quad, version 1 BeadChip in group 1 and Human OmniExpress 12, version 1 BeadChip platform in group 2). Analyses included genotype imputation at the TGFBR3 locus, association analysis of imputed data with correction for population substructure, subsequent meta-analysis of data for groups 1 and 2, and selective genotyping of independent cases (330) and controls (324) for replication. We also measured Tgfbr3 mRNA levels and performed TGFBR3/betaglycan immunostaining in rat fetal gubernaculum. RESULTS: We identified suggestive (p ≤ 1× 10(-4)) association of markers in/near TGFBR3, including rs9661103 (OR 1.40; 95% CI 1.20, 1.64; p = 2.71 × 10(-5)) and rs10782968 (OR 1.58; 95% CI 1.26, 1.98; p = 9.36 × 10(-5)) in groups 1 and 2, respectively. In subgroup analyses we observed strongest association of rs17576372 (OR 1.42; 95% CI 1.24, 1.60; p = 1.67 × 10(-4)) with proximal and rs11165059 (OR 1.32; 95% CI 1.15, 1.38; p = 9.42 × 10(-4)) with distal testis position, signals in strong linkage disequilibrium with rs9661103 and rs10782968, respectively. Association of the prior genome-wide association study signal (rs12082710) was marginal (OR 1.13; 95% CI 0.99, 1.28; p = 0.09 for group 1), and we were unable to replicate signals in our independent cohort. Tgfbr3/betaglycan was differentially expressed in wild-type and cryptorchid rat fetal gubernaculum. CONCLUSIONS: These data suggest complex or phenotype specific association of cryptorchidism with TGFBR3 and the gubernaculum as a potential target of TGFβ signaling. CI - Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved. FAU - Barthold, Julia S AU - Barthold JS AD - Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware; Division of Urology, Alfred I. duPont Hospital for Children, Wilmington, Delaware. Electronic address: jbarthol@nemours.org. FAU - Wang, Yanping AU - Wang Y AD - Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware. FAU - Kolon, Thomas F AU - Kolon TF AD - Division of Urology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. FAU - Kollin, Claude AU - Kollin C AD - Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. FAU - Nordenskjöld, Agneta AU - Nordenskjöld A AD - Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. FAU - Olivant Fisher, Alicia AU - Olivant Fisher A AD - Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware. FAU - Figueroa, T Ernesto AU - Figueroa TE AD - Division of Urology, Alfred I. duPont Hospital for Children, Wilmington, Delaware. FAU - BaniHani, Ahmad H AU - BaniHani AH AD - Division of Urology, Alfred I. duPont Hospital for Children, Wilmington, Delaware. FAU - Hagerty, Jennifer A AU - Hagerty JA AD - Division of Urology, Alfred I. duPont Hospital for Children, Wilmington, Delaware. FAU - Gonzalez, Ricardo AU - Gonzalez R AD - Division of Urology, Alfred I. duPont Hospital for Children, Wilmington, Delaware. FAU - Noh, Paul H AU - Noh PH AD - Division of Urology, Alfred I. duPont Hospital for Children, Wilmington, Delaware. FAU - Chiavacci, Rosetta M AU - Chiavacci RM AD - Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. FAU - Harden, Kisha R AU - Harden KR AD - Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. FAU - Abrams, Debra J AU - Abrams DJ AD - Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. FAU - Kim, Cecilia E AU - Kim CE AD - Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. FAU - Mateson, Abigail B AU - Mateson AB AD - Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware. FAU - Robbins, Alan K AU - Robbins AK AD - Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware. FAU - Li, Jin AU - Li J AD - Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. FAU - Akins, Robert E Jr AU - Akins RE Jr AD - Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware. FAU - Hakonarson, Hakon AU - Hakonarson H AD - Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.