Phenotype Specific Association of the TGFBR3 Locus with Nonsyndromic Cryptorchidism

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.