Phenotype Specific Association of the TGFBR3 Locus with Nonsyndromic Cryptorchidism

Abstract

Purpose Based on a genome-wide association study (GWAS) of testicular dysgenesis syndrome (TDS) reporting possible association with TGFBR3, we analyzed GWAS 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 2718 controls of European ancestry that were analyzed in 2 separate groups based on genotyping platform. Analyses included genotype imputation at the TGFBR3 locus, association analysis of imputed data with correction for population substructure, subsequent meta-analysis of Group 1 and 2 data and selective genotyping of independent cases (n=330) and controls (n=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, 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, CI 1.24,1.60; p=1.67×10−4) with proximal and rs11165059 (OR 1.32, 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 GWAS signal (rs12082710) was marginal (OR 1.13, 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.

Molecular genetics of hypospadias and cryptorchidism recent developments

“…In a large GWAS case‐control study of boys with isolated cryptorchidism compared to normal boys, Barthold et al uncovered 20 loci. One hundred and twenty‐seven top loci were identified in more severe phenotypes.…”

Genetic, Maternal, and Environmental Risk Factors for Cryptorchidism: An Update

“…21 In our recent GWAS of nonsyndromic cryptorchidism in subjects of European ancestry that included 844 cases and 2,718 controls (the latter at least 7 years of age to exclude cases of acquired cryptorchidism), whole genome imputation and meta-analyses were performed for a combined analysis of two separate case-control Groups (1 and 2) genotyped on different platforms. 18,70 In an initial analysis focusing on the TGFBR3 locus, 70 we identified suggestive (p 1 Â 10 4 ) association of markers in/near TGFBR3 including rs9661103 (OR: 1.40; 95% CI: 1.20, 1.64; p ¼ 2.71 Â 10 À5 ) and rs10782968 (OR: 1.58; CI: 1.26, 1.98; p ¼ 9.36 Â 10 À5 ) in Groups 1 and 2, respectively, and differential association of TGFBR3-associated SNPs with different cryptorchidism subphenotypes (proximal vs. distal testis position). We also identified differential expression of TGFBR3 and betaglycan, its encoded protein, in wild type and cryptorchid rat fetal gubernaculum.…”

Transcriptomic Analysis of Testicular Gene Expression in Normal and Cryptorchid Horses

“…Mutation of INSL3 results in bilateral intraabdominal cryptorchidism in humans and mice [7,8]. Furthermore, polymorphisms in the androgen receptor (AR), TGFBR3, and Hoxa11 genes and in genetic loci coding for cytoskeleton-associated proteins have been recognized as contributing risk factors for cryptorchidism [13][14][15][16][17]. A chance observation of high incidences of cryptorchidism in humans and animals led to the decision to study impaired testicular descent.…”