Background Testicular dysgenesis syndrome (TDS) is a common disease that links testicular germ cell cancer, cryptorchidism and some cases of hypospadias and male infertility with impaired development of the testis. The incidence of these disorders has increased over the last few decades, and testicular cancer now affects 1% of the Danish and Norwegian male population.
Methods To identify genetic variants that span the four TDS phenotypes, the authors performed a genome-wide association study (GWAS) using Affymetrix Human SNP Array 6.0 to screen 488 patients with symptoms of TDS and 439 selected controls with excellent reproductive health. Furthermore, they developed a novel integrative method that combines GWAS data with other TDS-relevant data types and identified additional TDS markers. The most significant findings were replicated in an independent cohort of 671 Nordic men.
Results Markers located in the region of TGFBR3 and BMP7 showed association with all TDS phenotypes in both the discovery and replication cohorts. An immunohistochemistry investigation confirmed the presence of transforming growth factor β receptor type III (TGFBR3) in peritubular and Leydig cells, in both fetal and adult testis. Single-nucleotide polymorphisms in the KITLG gene showed significant associations, but only with testicular cancer.
Conclusions The association of single-nucleotide polymorphisms in the TGFBR3 and BMP7 genes, which belong to the transforming growth factor β signalling pathway, suggests a role for this pathway in the pathogenesis of TDS. Integrating data from multiple layers can highlight findings in GWAS that are biologically relevant despite having border significance at currently accepted statistical levels.
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MDD, NW and DE contributed equally to this work.
Funding This work was supported by the Villum Kann Rasmussen Foundation, a NABIIT grant from the Danish Strategic Research Council, the Novo Nordisk Foundation, the Academy of Finland, Sigrid Juselius Foundation, Foundation for Paediatric Research, Turku University Hospital, the European Commission (FP7/2008-2012: DEER 212844), the Swedish Cancer Society (CAN 2009/817), Gunnar Nissons Cancer Foundation, Malmö University Hospitals Cancer Foundation and King Gustaf V's Jubilee Fund for Cancer Research.
Competing interests None.
Patient consent Obtained.
Ethics approval The local ethics committees in Denmark, Sweden and Finland.
Provenance and peer review Not commissioned; externally peer reviewed.
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