A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation
BackgroundTesticular 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 testicul...
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| creator | Dalgaard, Marlene D Weinhold, Nils Edsgärd, Daniel Silver, Jeremy D Pers, Tune H Nielsen, John E Jørgensen, Niels Juul, Anders Gerds, Thomas A Giwercman, Aleksander Giwercman, Yvonne L Cohn-Cedermark, Gabriella Virtanen, Helena E Toppari, Jorma Daugaard, Gedske Jensen, Thomas S Brunak, Søren Rajpert-De Meyts, Ewa Skakkebæk, Niels E Leffers, Henrik Gupta, Ramneek |
| description | BackgroundTesticular 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.MethodsTo 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.ResultsMarkers 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.ConclusionsThe 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. |
| doi_str_mv | 10.1136/jmedgenet-2011-100174 |
| format | Article |
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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.MethodsTo 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.ResultsMarkers 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.ConclusionsThe 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.</description><identifier>ISSN: 0022-2593</identifier><identifier>EISSN: 1468-6244</identifier><identifier>DOI: 10.1136/jmedgenet-2011-100174</identifier><identifier>PMID: 22140272</identifier><identifier>CODEN: JMDGAE</identifier><language>eng</language><publisher>London: BMJ Publishing Group Ltd</publisher><subject>Adult ; Basic Medicine ; Biological and medical sciences ; Biology ; Bone Morphogenetic Protein 7 - genetics ; Bone Morphogenetic Protein 7 - metabolism ; Cancer ; cancer: urological ; Case-Control Studies ; chromosomal ; Cohort Studies ; Complex Traits ; Cryptorchidism ; developmental ; diabetes ; endocrinology ; epidemiology ; Gene Expression ; Genes ; genetic epidemiology ; Genetic Markers ; Genetic Predisposition to Disease ; genetics ; genome-wide ; Genome-Wide Association Study ; Genomes ; Genotype ; Genotype & phenotype ; Gonadal Dysgenesis - genetics ; Gonadal Dysgenesis - metabolism ; GWAS ; Gynecology. Andrology. Obstetrics ; Humans ; Hypotheses ; Infertility ; Linkage Disequilibrium ; Male ; Medical and Health Sciences ; Medical Genetics ; Medical sciences ; Medicin och hälsovetenskap ; Medicinsk genetik ; Medicinska och farmaceutiska grundvetenskaper ; Neoplasms, Germ Cell and Embryonal - genetics ; Neoplasms, Germ Cell and Embryonal - metabolism ; oncology ; Polymorphism, Single Nucleotide ; Protein Interaction Maps ; Proteins ; Proteoglycans - genetics ; Proteoglycans - metabolism ; Quality control ; Receptors, Transforming Growth Factor beta - genetics ; Receptors, Transforming Growth Factor beta - metabolism ; reproductive medicine ; Sperm ; Stem Cell Factor - genetics ; Stem Cell Factor - metabolism ; systems biology ; TDS ; Testicular Neoplasms - genetics ; Testicular Neoplasms - metabolism ; Testis - metabolism ; Testis - pathology ; testis cancer ; Tumors</subject><ispartof>Journal of medical genetics, 2012-01, Vol.49 (1), p.58-65</ispartof><rights>2011, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.</rights><rights>2015 INIST-CNRS</rights><rights>Copyright: 2011 (c) 2011, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.</rights><rights>2011, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b654t-62bd5007bc2fe222bcb3761f07b660a3b88f42aa03d13164f289b24d6ae7b2cf3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://jmg.bmj.com/content/49/1/58.full.pdf$$EPDF$$P50$$Gbmj$$H</linktopdf><linktohtml>$$Uhttps://jmg.bmj.com/content/49/1/58.full$$EHTML$$P50$$Gbmj$$H</linktohtml><link.rule.ids>114,115,230,314,550,776,780,881,3183,23550,27901,27902,77343,77374</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25353828$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22140272$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://lup.lub.lu.se/record/2333817$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:123769468$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Dalgaard, Marlene D</creatorcontrib><creatorcontrib>Weinhold, Nils</creatorcontrib><creatorcontrib>Edsgärd, Daniel</creatorcontrib><creatorcontrib>Silver, Jeremy D</creatorcontrib><creatorcontrib>Pers, Tune H</creatorcontrib><creatorcontrib>Nielsen, John E</creatorcontrib><creatorcontrib>Jørgensen, Niels</creatorcontrib><creatorcontrib>Juul, Anders</creatorcontrib><creatorcontrib>Gerds, Thomas A</creatorcontrib><creatorcontrib>Giwercman, Aleksander</creatorcontrib><creatorcontrib>Giwercman, Yvonne L</creatorcontrib><creatorcontrib>Cohn-Cedermark, Gabriella</creatorcontrib><creatorcontrib>Virtanen, Helena E</creatorcontrib><creatorcontrib>Toppari, Jorma</creatorcontrib><creatorcontrib>Daugaard, Gedske</creatorcontrib><creatorcontrib>Jensen, Thomas S</creatorcontrib><creatorcontrib>Brunak, Søren</creatorcontrib><creatorcontrib>Rajpert-De Meyts, Ewa</creatorcontrib><creatorcontrib>Skakkebæk, Niels E</creatorcontrib><creatorcontrib>Leffers, Henrik</creatorcontrib><creatorcontrib>Gupta, Ramneek</creatorcontrib><title>A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation</title><title>Journal of medical genetics</title><addtitle>J Med Genet</addtitle><description>BackgroundTesticular 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.MethodsTo 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.ResultsMarkers 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.ConclusionsThe 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.</description><subject>Adult</subject><subject>Basic Medicine</subject><subject>Biological and medical sciences</subject><subject>Biology</subject><subject>Bone Morphogenetic Protein 7 - genetics</subject><subject>Bone Morphogenetic Protein 7 - metabolism</subject><subject>Cancer</subject><subject>cancer: urological</subject><subject>Case-Control Studies</subject><subject>chromosomal</subject><subject>Cohort Studies</subject><subject>Complex Traits</subject><subject>Cryptorchidism</subject><subject>developmental</subject><subject>diabetes</subject><subject>endocrinology</subject><subject>epidemiology</subject><subject>Gene Expression</subject><subject>Genes</subject><subject>genetic epidemiology</subject><subject>Genetic Markers</subject><subject>Genetic Predisposition to Disease</subject><subject>genetics</subject><subject>genome-wide</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>Gonadal Dysgenesis - genetics</subject><subject>Gonadal Dysgenesis - metabolism</subject><subject>GWAS</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>Hypotheses</subject><subject>Infertility</subject><subject>Linkage Disequilibrium</subject><subject>Male</subject><subject>Medical and Health Sciences</subject><subject>Medical Genetics</subject><subject>Medical sciences</subject><subject>Medicin och hälsovetenskap</subject><subject>Medicinsk genetik</subject><subject>Medicinska och farmaceutiska grundvetenskaper</subject><subject>Neoplasms, Germ Cell and Embryonal - genetics</subject><subject>Neoplasms, Germ Cell and Embryonal - metabolism</subject><subject>oncology</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Protein Interaction Maps</subject><subject>Proteins</subject><subject>Proteoglycans - genetics</subject><subject>Proteoglycans - metabolism</subject><subject>Quality control</subject><subject>Receptors, Transforming Growth Factor beta - genetics</subject><subject>Receptors, Transforming Growth Factor beta - metabolism</subject><subject>reproductive medicine</subject><subject>Sperm</subject><subject>Stem Cell Factor - genetics</subject><subject>Stem Cell Factor - metabolism</subject><subject>systems biology</subject><subject>TDS</subject><subject>Testicular Neoplasms - genetics</subject><subject>Testicular Neoplasms - metabolism</subject><subject>Testis - metabolism</subject><subject>Testis - pathology</subject><subject>testis cancer</subject><subject>Tumors</subject><issn>0022-2593</issn><issn>1468-6244</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>D8T</sourceid><recordid>eNqNkl2L1DAUhoso7rj6E5SAyF5V8932RlgG1xWGFUQX70LSprOZaZvZJHWcC_-7p8446wqCF6Hl5Dlv3vORZc8Jfk0Ik29WvW2WdrApp5iQnGBMCv4gmxEuy1xSzh9mM4wpzamo2En2JMYVIKwg8nF2QinhmBZ0lv04R6Die5tvXWORjtHXTifnBxTT2OyQb1FvB7R16QbFXb9Jvo9TMNmYXD12OqBmFycn0UUghiaAGtJDg1yKCAxufVgj43znlzvkhmTDJtj0642n2aNWd9E-O3xPsy8X7z7PL_PFx_cf5ueL3EjBE5RjGoFxYWraWkqpqQ0rJGkhIiXWzJRly6nWmDWEEclbWlaG8kZqWxhat-w0y_e6cWs3o1Gb4Hoddsprpw6hNfxZJThmTAK_-CffjRs4Bs6UwFklwA5XRcUbxTEWqmoFUbiRra5lYQkTIPd2LwdaMLbaDino7p7q_ZvB3ail_6YYLTkjDATODgLB347QedW7WNuu04P1Y1QVIRVnQk5PvfyLXPkxDNBcRYqSwOCxnOoTe6oOPsZg26MXgtW0Xuq4XmpaL7VfL8h78Wchx6zf-wTAqwOgY627NuihdvGOE9CNkpZ3A3Ex2e_Hex3WShasEOrqeq6-Xn26ZDB3dQ083vOmX_2n159js_0I</recordid><startdate>20120101</startdate><enddate>20120101</enddate><creator>Dalgaard, Marlene D</creator><creator>Weinhold, Nils</creator><creator>Edsgärd, Daniel</creator><creator>Silver, Jeremy D</creator><creator>Pers, Tune H</creator><creator>Nielsen, John E</creator><creator>Jørgensen, Niels</creator><creator>Juul, Anders</creator><creator>Gerds, Thomas A</creator><creator>Giwercman, Aleksander</creator><creator>Giwercman, Yvonne L</creator><creator>Cohn-Cedermark, Gabriella</creator><creator>Virtanen, Helena E</creator><creator>Toppari, Jorma</creator><creator>Daugaard, Gedske</creator><creator>Jensen, Thomas S</creator><creator>Brunak, Søren</creator><creator>Rajpert-De Meyts, Ewa</creator><creator>Skakkebæk, Niels E</creator><creator>Leffers, Henrik</creator><creator>Gupta, Ramneek</creator><general>BMJ Publishing Group Ltd</general><general>BMJ Publishing Group</general><general>BMJ Publishing Group LTD</general><general>BMJ Group</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D95</scope><scope>D8T</scope><scope>ZZAVC</scope></search><sort><creationdate>20120101</creationdate><title>A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation</title><author>Dalgaard, Marlene D ; Weinhold, Nils ; Edsgärd, Daniel ; Silver, Jeremy D ; Pers, Tune H ; Nielsen, John E ; Jørgensen, Niels ; Juul, Anders ; Gerds, Thomas A ; Giwercman, Aleksander ; Giwercman, Yvonne L ; Cohn-Cedermark, Gabriella ; Virtanen, Helena E ; Toppari, Jorma ; Daugaard, Gedske ; Jensen, Thomas S ; Brunak, Søren ; Rajpert-De Meyts, Ewa ; Skakkebæk, Niels E ; Leffers, Henrik ; Gupta, Ramneek</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b654t-62bd5007bc2fe222bcb3761f07b660a3b88f42aa03d13164f289b24d6ae7b2cf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adult</topic><topic>Basic Medicine</topic><topic>Biological and medical sciences</topic><topic>Biology</topic><topic>Bone Morphogenetic Protein 7 - genetics</topic><topic>Bone Morphogenetic Protein 7 - metabolism</topic><topic>Cancer</topic><topic>cancer: urological</topic><topic>Case-Control Studies</topic><topic>chromosomal</topic><topic>Cohort Studies</topic><topic>Complex Traits</topic><topic>Cryptorchidism</topic><topic>developmental</topic><topic>diabetes</topic><topic>endocrinology</topic><topic>epidemiology</topic><topic>Gene Expression</topic><topic>Genes</topic><topic>genetic epidemiology</topic><topic>Genetic Markers</topic><topic>Genetic Predisposition to Disease</topic><topic>genetics</topic><topic>genome-wide</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Genotype</topic><topic>Genotype & phenotype</topic><topic>Gonadal Dysgenesis - genetics</topic><topic>Gonadal Dysgenesis - metabolism</topic><topic>GWAS</topic><topic>Gynecology. 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Obstetrics</topic><topic>Humans</topic><topic>Hypotheses</topic><topic>Infertility</topic><topic>Linkage Disequilibrium</topic><topic>Male</topic><topic>Medical and Health Sciences</topic><topic>Medical Genetics</topic><topic>Medical sciences</topic><topic>Medicin och hälsovetenskap</topic><topic>Medicinsk genetik</topic><topic>Medicinska och farmaceutiska grundvetenskaper</topic><topic>Neoplasms, Germ Cell and Embryonal - genetics</topic><topic>Neoplasms, Germ Cell and Embryonal - metabolism</topic><topic>oncology</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Protein Interaction Maps</topic><topic>Proteins</topic><topic>Proteoglycans - genetics</topic><topic>Proteoglycans - metabolism</topic><topic>Quality control</topic><topic>Receptors, Transforming Growth Factor beta - genetics</topic><topic>Receptors, Transforming Growth Factor beta - metabolism</topic><topic>reproductive medicine</topic><topic>Sperm</topic><topic>Stem Cell Factor - genetics</topic><topic>Stem Cell Factor - metabolism</topic><topic>systems biology</topic><topic>TDS</topic><topic>Testicular Neoplasms - genetics</topic><topic>Testicular Neoplasms - metabolism</topic><topic>Testis - metabolism</topic><topic>Testis - pathology</topic><topic>testis cancer</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dalgaard, Marlene D</creatorcontrib><creatorcontrib>Weinhold, Nils</creatorcontrib><creatorcontrib>Edsgärd, Daniel</creatorcontrib><creatorcontrib>Silver, Jeremy D</creatorcontrib><creatorcontrib>Pers, Tune H</creatorcontrib><creatorcontrib>Nielsen, John E</creatorcontrib><creatorcontrib>Jørgensen, Niels</creatorcontrib><creatorcontrib>Juul, Anders</creatorcontrib><creatorcontrib>Gerds, Thomas A</creatorcontrib><creatorcontrib>Giwercman, Aleksander</creatorcontrib><creatorcontrib>Giwercman, Yvonne L</creatorcontrib><creatorcontrib>Cohn-Cedermark, Gabriella</creatorcontrib><creatorcontrib>Virtanen, Helena E</creatorcontrib><creatorcontrib>Toppari, Jorma</creatorcontrib><creatorcontrib>Daugaard, Gedske</creatorcontrib><creatorcontrib>Jensen, Thomas S</creatorcontrib><creatorcontrib>Brunak, Søren</creatorcontrib><creatorcontrib>Rajpert-De Meyts, Ewa</creatorcontrib><creatorcontrib>Skakkebæk, Niels E</creatorcontrib><creatorcontrib>Leffers, Henrik</creatorcontrib><creatorcontrib>Gupta, Ramneek</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Lunds universitet</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Journal of medical genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dalgaard, Marlene D</au><au>Weinhold, Nils</au><au>Edsgärd, Daniel</au><au>Silver, Jeremy D</au><au>Pers, Tune H</au><au>Nielsen, John E</au><au>Jørgensen, Niels</au><au>Juul, Anders</au><au>Gerds, Thomas A</au><au>Giwercman, Aleksander</au><au>Giwercman, Yvonne L</au><au>Cohn-Cedermark, Gabriella</au><au>Virtanen, Helena E</au><au>Toppari, Jorma</au><au>Daugaard, Gedske</au><au>Jensen, Thomas S</au><au>Brunak, Søren</au><au>Rajpert-De Meyts, Ewa</au><au>Skakkebæk, Niels E</au><au>Leffers, Henrik</au><au>Gupta, Ramneek</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation</atitle><jtitle>Journal of medical genetics</jtitle><addtitle>J Med Genet</addtitle><date>2012-01-01</date><risdate>2012</risdate><volume>49</volume><issue>1</issue><spage>58</spage><epage>65</epage><pages>58-65</pages><issn>0022-2593</issn><eissn>1468-6244</eissn><coden>JMDGAE</coden><abstract>BackgroundTesticular 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.MethodsTo 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.ResultsMarkers 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.ConclusionsThe 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.</abstract><cop>London</cop><pub>BMJ Publishing Group Ltd</pub><pmid>22140272</pmid><doi>10.1136/jmedgenet-2011-100174</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2593 |
| ispartof | Journal of medical genetics, 2012-01, Vol.49 (1), p.58-65 |
| issn | 0022-2593 1468-6244 |
| language | eng |
| recordid | cdi_swepub_primary_oai_swepub_ki_se_540336 |
| source | MEDLINE; BMJ Journals - NESLi2; SWEPUB Freely available online |
| subjects | Adult Basic Medicine Biological and medical sciences Biology Bone Morphogenetic Protein 7 - genetics Bone Morphogenetic Protein 7 - metabolism Cancer cancer: urological Case-Control Studies chromosomal Cohort Studies Complex Traits Cryptorchidism developmental diabetes endocrinology epidemiology Gene Expression Genes genetic epidemiology Genetic Markers Genetic Predisposition to Disease genetics genome-wide Genome-Wide Association Study Genomes Genotype Genotype & phenotype Gonadal Dysgenesis - genetics Gonadal Dysgenesis - metabolism GWAS Gynecology. Andrology. Obstetrics Humans Hypotheses Infertility Linkage Disequilibrium Male Medical and Health Sciences Medical Genetics Medical sciences Medicin och hälsovetenskap Medicinsk genetik Medicinska och farmaceutiska grundvetenskaper Neoplasms, Germ Cell and Embryonal - genetics Neoplasms, Germ Cell and Embryonal - metabolism oncology Polymorphism, Single Nucleotide Protein Interaction Maps Proteins Proteoglycans - genetics Proteoglycans - metabolism Quality control Receptors, Transforming Growth Factor beta - genetics Receptors, Transforming Growth Factor beta - metabolism reproductive medicine Sperm Stem Cell Factor - genetics Stem Cell Factor - metabolism systems biology TDS Testicular Neoplasms - genetics Testicular Neoplasms - metabolism Testis - metabolism Testis - pathology testis cancer Tumors |
| title | A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation |
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