• PMID: 22140272
• Gene Name: BMP7
• Condition: Testicular dysgenesis syndrome (TDS)
• Association: The association of single-nucleotide polymorphisms in the TGFBR3 and BMP7 genes, which belong to the transforming growth factor ? signalling pathway, suggests a role for this pathway in the pathogenesis of TDS. Integrating data from multiple layers can hi
• Population size: 1198
• Population details: 1198 (488 patients with symptoms of TDS, 439 selected controls, 671 Nordic men)
• Sex: Male
• Infertility type: Male infertility
• Associated genes: TGFBR3, BMP7
• Other associated phenotypes: Testicular dysgenesis syndrome (TDS)

A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation

Dalgaard MD, Weinhold N, Edsgärd D, Silver JD, Pers TH, Nielsen JE, Jørgensen N, Juul A, Gerds TA, Giwercman A, Giwercman YL, Cohn-Cedermark G, Virtanen HE, Toppari J, Daugaard G, Jensen TS, Brunak S, Rajpert-De Meyts E, Skakkebæk NE, Leffers H, Gupta R.

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. FAU - Dalgaard, Marlene D AU - Dalgaard MD AD - Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark. FAU - Weinhold, Nils AU - Weinhold N FAU - Edsgärd, Daniel AU - Edsgärd D FAU - Silver, Jeremy D AU - Silver JD FAU - Pers, Tune H AU - Pers TH FAU - Nielsen, John E AU - Nielsen JE FAU - Jørgensen, Niels AU - Jørgensen N FAU - Juul, Anders AU - Juul A FAU - Gerds, Thomas A AU - Gerds TA FAU - Giwercman, Aleksander AU - Giwercman A FAU - Giwercman, Yvonne L AU - Giwercman YL FAU - Cohn-Cedermark, Gabriella AU - Cohn-Cedermark G FAU - Virtanen, Helena E AU - Virtanen HE FAU - Toppari, Jorma AU - Toppari J FAU - Daugaard, Gedske AU - Daugaard G FAU - Jensen, Thomas S AU - Jensen TS FAU - Brunak, Søren AU - Brunak S FAU - Rajpert-De Meyts, Ewa AU - Rajpert-De Meyts E FAU - Skakkebæk, Niels E AU - Skakkebæk NE FAU - Leffers, Henrik AU - Leffers H