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

Dalgaard, Marlene D.; Weinhold, Nils; Edsgard, Daniel; Silver, Jeremy D.; Pers, Tune H.; Nielsen, John E.; Jorgensen, Niels; Juul, Anders; Gerds, Thomas A. and Giwercman, Aleksander LU , et al. (2012) In Journal of Medical Genetics 49(1). p.58-65
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... (More)
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 beta 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 b 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. (Less)
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Journal of Medical Genetics
volume
49
issue
1
pages
58 - 65
publisher
BMJ Publishing Group
external identifiers
  • wos:000298400500009
  • scopus:84856013409
ISSN
0022-2593
DOI
10.1136/jmedgenet-2011-100174
language
English
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yes
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4395bcb4-794d-4005-9f51-0d6fac67e135 (old id 2333817)
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2012-02-01 07:40:35
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2017-07-23 04:05:29
@article{4395bcb4-794d-4005-9f51-0d6fac67e135,
  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 beta 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 b 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.},
  author       = {Dalgaard, Marlene D. and Weinhold, Nils and Edsgard, Daniel and Silver, Jeremy D. and Pers, Tune H. and Nielsen, John E. and Jorgensen, Niels and Juul, Anders and Gerds, Thomas A. and Giwercman, Aleksander and Giwercman, Yvonne and Cohn-Cedermark, Gabriella and Virtanen, Helena E. and Toppari, Jorma and Daugaard, Gedske and Jensen, Thomas S. and Brunak, Soren and Rajpert-De Meyts, Ewa and Skakkebk, Niels E. and Leffers, Henrik and Gupta, Ramneek},
  issn         = {0022-2593},
  language     = {eng},
  number       = {1},
  pages        = {58--65},
  publisher    = {BMJ Publishing Group},
  series       = {Journal of Medical Genetics},
  title        = {A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation},
  url          = {http://dx.doi.org/10.1136/jmedgenet-2011-100174},
  volume       = {49},
  year         = {2012},
}