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

Marlene D. Dalgaard; Nils Weinhold; Daniel Edsgärd; Jeremy David Silver; Tune H. Pers; John E. Nielsen; Niels Jørgensen; Anders Juul; Thomas Alexander Gerds; Aleksander Giwercman; Yvonne L. Giwercman; Gabriella Cohn-Cedermark; Helena E. Virtanen; Jorma Toppari; Gedske Daugaard; Thomas Skøt Jensen; Søren Brunak; Ewa Rajpert-De Meyts; Niels E. Skakkebæk; Henrik Leffers; Ramneek Gupta

doi:10.1136/jmedgenet-2011-100174

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

Marlene D. Dalgaard, Nils Weinhold, Daniel Edsgärd, Jeremy David Silver, Tune H. Pers, John E. Nielsen, Niels Jørgensen, Anders Juul, Thomas Alexander Gerds, Aleksander Giwercman, Yvonne L. Giwercman, Gabriella Cohn-Cedermark, Helena E. Virtanen, Jorma Toppari, Gedske Daugaard, Thomas Skøt Jensen, Søren Brunak, Ewa Rajpert-De Meyts, Niels E. Skakkebæk, Henrik LeffersRamneek Gupta

83 Citations (Scopus)

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 TDSrelevant 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.

Original language	English
Journal	Journal of Medical Genetics
Volume	49
Issue number	1
Pages (from-to)	58-65
Number of pages	8
ISSN	0022-2593
DOIs	https://doi.org/10.1136/jmedgenet-2011-100174
Publication status	Published - Jan 2012

Keywords

Adult
Bone Morphogenetic Protein 7
Case-Control Studies
Cohort Studies
Gene Expression
Genetic Markers
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Gonadal Dysgenesis
Humans
Linkage Disequilibrium
Male
Neoplasms, Germ Cell and Embryonal
Polymorphism, Single Nucleotide
Protein Interaction Maps
Proteoglycans
Receptors, Transforming Growth Factor beta
Stem Cell Factor
Testicular Neoplasms
Testis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/jmedgenet-2011-100174

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Dalgaard, M. D., Weinhold, N., Edsgärd, D., Silver, J. D., Pers, T. H., Nielsen, J. E., Jørgensen, N., Juul, A., Gerds, T. A., Giwercman, A., Giwercman, Y. L., Cohn-Cedermark, G., Virtanen, H. E., Toppari, J., Daugaard, G., Jensen, T. S., Brunak, S., Rajpert-De Meyts, E., Skakkebæk, N. E., ... Gupta, R. (2012). A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation. Journal of Medical Genetics, 49(1), 58-65. https://doi.org/10.1136/jmedgenet-2011-100174

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 2012, 'A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation', Journal of Medical Genetics, vol. 49, no. 1, pp. 58-65. https://doi.org/10.1136/jmedgenet-2011-100174

@article{4ec045c832ef43a8847a4996bf0c4a4a,

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 TDSrelevant 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.",

keywords = "Adult, Bone Morphogenetic Protein 7, Case-Control Studies, Cohort Studies, Gene Expression, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Gonadal Dysgenesis, Humans, Linkage Disequilibrium, Male, Neoplasms, Germ Cell and Embryonal, Polymorphism, Single Nucleotide, Protein Interaction Maps, Proteoglycans, Receptors, Transforming Growth Factor beta, Stem Cell Factor, Testicular Neoplasms, Testis",

author = "Dalgaard, {Marlene D.} and Nils Weinhold and Daniel Edsg{\"a}rd and Silver, {Jeremy David} and Pers, {Tune H.} and Nielsen, {John E.} and Niels J{\o}rgensen and Anders Juul and Gerds, {Thomas Alexander} and Aleksander Giwercman and Giwercman, {Yvonne L.} and Gabriella Cohn-Cedermark and Virtanen, {Helena E.} and Jorma Toppari and Gedske Daugaard and Jensen, {Thomas Sk{\o}t} and S{\o}ren Brunak and {Rajpert-De Meyts}, Ewa and Skakkeb{\ae}k, {Niels E.} and Henrik Leffers and Ramneek Gupta",

year = "2012",

month = jan,

doi = "10.1136/jmedgenet-2011-100174",

language = "English",

volume = "49",

pages = "58--65",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "B M J Group",

number = "1",

}

TY - JOUR

T1 - A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation

AU - Dalgaard, Marlene D.

AU - Weinhold, Nils

AU - Edsgärd, Daniel

AU - Silver, Jeremy David

AU - Pers, Tune H.

AU - Nielsen, John E.

AU - Jørgensen, Niels

AU - Juul, Anders

AU - Gerds, Thomas Alexander

AU - Giwercman, Aleksander

AU - Giwercman, Yvonne L.

AU - Cohn-Cedermark, Gabriella

AU - Virtanen, Helena E.

AU - Toppari, Jorma

AU - Daugaard, Gedske

AU - Jensen, Thomas Skøt

AU - Brunak, Søren

AU - Rajpert-De Meyts, Ewa

AU - Skakkebæk, Niels E.

AU - Leffers, Henrik

AU - Gupta, Ramneek

PY - 2012/1

Y1 - 2012/1

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 TDSrelevant 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.

AB - 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 TDSrelevant 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.

KW - Adult

KW - Bone Morphogenetic Protein 7

KW - Case-Control Studies

KW - Cohort Studies

KW - Gene Expression

KW - Genetic Markers

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Gonadal Dysgenesis

KW - Humans

KW - Linkage Disequilibrium

KW - Male

KW - Neoplasms, Germ Cell and Embryonal

KW - Polymorphism, Single Nucleotide

KW - Protein Interaction Maps

KW - Proteoglycans

KW - Receptors, Transforming Growth Factor beta

KW - Stem Cell Factor

KW - Testicular Neoplasms

KW - Testis

U2 - 10.1136/jmedgenet-2011-100174

DO - 10.1136/jmedgenet-2011-100174

M3 - Journal article

C2 - 22140272

SN - 0022-2593

VL - 49

SP - 58

EP - 65

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

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