title: A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation.
abstract: 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.
authors.affiliation: Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Marlene D
authors.initials: MD
authors.lastname: Dalgaard
authors.forename: Nils
authors.initials: N
authors.lastname: Weinhold
authors.forename: Daniel
authors.initials: D
authors.lastname: Edsgärd
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Silver
authors.forename: Tune H
authors.initials: TH
authors.lastname: Pers
authors.forename: John E
authors.initials: JE
authors.lastname: Nielsen
authors.forename: Niels
authors.initials: N
authors.lastname: Jørgensen
authors.forename: Anders
authors.initials: A
authors.lastname: Juul
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gerds
authors.forename: Aleksander
authors.initials: A
authors.lastname: Giwercman
authors.forename: Yvonne L
authors.initials: YL
authors.lastname: Giwercman
authors.forename: Gabriella
authors.initials: G
authors.lastname: Cohn-Cedermark
authors.forename: Helena E
authors.initials: HE
authors.lastname: Virtanen
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.forename: Gedske
authors.initials: G
authors.lastname: Daugaard
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Jensen
authors.forename: Søren
authors.initials: S
authors.lastname: Brunak
authors.forename: Ewa
authors.initials: E
authors.lastname: Rajpert-De Meyts
authors.forename: Niels E
authors.initials: NE
authors.lastname: Skakkebæk
authors.forename: Henrik
authors.initials: H
authors.lastname: Leffers
authors.forename: Ramneek
authors.initials: R
authors.lastname: Gupta
mesh_terms: D000328:Adult; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D015870:Gene Expression; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006059:Gonadal Dysgenesis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D060066:Protein Interaction Maps; D011509:Proteoglycans / Q000235:genetics* / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D019089:Stem Cell Factor / Q000235:genetics* / Q000378:metabolism; D013736:Testicular Neoplasms / Q000235:genetics* / Q000378:metabolism; D013737:Testis / Q000378:metabolism / Q000473:pathology
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D005819:Genetic Markers; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D019089:Stem Cell Factor; C071736:betaglycan