TY - JOUR T1 - A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation JF - Journal of Medical Genetics JO - J Med Genet SP - 58 LP - 65 DO - 10.1136/jmedgenet-2011-100174 VL - 49 IS - 1 AU - Marlene D Dalgaard AU - Nils Weinhold AU - Daniel Edsgärd AU - Jeremy D Silver AU - Tune H Pers AU - John E Nielsen AU - Niels Jørgensen AU - Anders Juul AU - Thomas A Gerds AU - Aleksander Giwercman AU - Yvonne L Giwercman AU - Gabriella Cohn-Cedermark AU - Helena E Virtanen AU - Jorma Toppari AU - Gedske Daugaard AU - Thomas S Jensen AU - Søren Brunak AU - Ewa Rajpert-De Meyts AU - Niels E Skakkebæk AU - Henrik Leffers AU - Ramneek Gupta Y1 - 2012/01/01 UR - http://jmg.bmj.com/content/49/1/58.abstract N2 - 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. ER -