Genome-wide association analyses identify variants in developmental genes associated with hypospadias
Frank Geller and colleagues report the results of a large genome-wide association study of hypospadias. They identify 18 susceptibility regions for this common congenital condition, many of which harbor genes important for embryonic development. Hypospadias is a common congenital condition in boys i...
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Veröffentlicht in: | Nature genetics 2014-09, Vol.46 (9), p.957-963 |
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creator | Geller, Frank Feenstra, Bjarke Carstensen, Lisbeth Pers, Tune H van Rooij, Iris A L M Körberg, Izabella Baranowska Choudhry, Shweta Karjalainen, Juha M Schnack, Tine H Hollegaard, Mads V Feitz, Wout F J Roeleveld, Nel Hougaard, David M Hirschhorn, Joel N Franke, Lude Baskin, Laurence S Nordenskjöld, Agneta van der Zanden, Loes F M Melbye, Mads |
description | Frank Geller and colleagues report the results of a large genome-wide association study of hypospadias. They identify 18 susceptibility regions for this common congenital condition, many of which harbor genes important for embryonic development.
Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1,812 controls from Denmark, the Netherlands and Sweden, 18 genomic regions showed independent association with
P
< 5 × 10
−8
. Together, these loci explain 9% of the liability to developing this condition. Several of the identified regions harbor genes with key roles in embryonic development (including
HOXA4
,
IRX5
,
IRX6
and
EYA1
). Subsequent pathway analysis with GRAIL and DEPICT provided additional insight into possible genetic mechanisms causing hypospadias. |
doi_str_mv | 10.1038/ng.3063 |
format | Article |
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Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1,812 controls from Denmark, the Netherlands and Sweden, 18 genomic regions showed independent association with
P
< 5 × 10
−8
. Together, these loci explain 9% of the liability to developing this condition. Several of the identified regions harbor genes with key roles in embryonic development (including
HOXA4
,
IRX5
,
IRX6
and
EYA1
). Subsequent pathway analysis with GRAIL and DEPICT provided additional insight into possible genetic mechanisms causing hypospadias.</description><identifier>ISSN: 1061-4036</identifier><identifier>EISSN: 1546-1718</identifier><identifier>DOI: 10.1038/ng.3063</identifier><identifier>PMID: 25108383</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>45 ; 45/43 ; 45/88 ; 631/208/205/2138 ; 692/699/2768 ; Agriculture ; Animal Genetics and Genomics ; Biomedicine ; Cancer Research ; Case-Control Studies ; Councils ; Denmark ; Development and progression ; Embryonic growth stage ; Female ; Gene Function ; Genes ; Genes, Developmental ; Genetic aspects ; Genetic Predisposition to Disease ; Genome-wide association studies ; Genome-Wide Association Study - methods ; Genomes ; Genomics ; Genotype ; Human Genetics ; Humans ; Hypospadias ; Hypospadias - genetics ; Identification and classification ; Male ; Methods ; Netherlands ; Polymorphism, Single Nucleotide ; Quantitative trait loci ; Studies ; Sweden</subject><ispartof>Nature genetics, 2014-09, Vol.46 (9), p.957-963</ispartof><rights>Springer Nature Limited 2014</rights><rights>COPYRIGHT 2014 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Sep 2014</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c546t-52f10aec6ba13d1dac54294b0687d17b8f979524a055e595856d73cd2b94bece3</citedby><cites>FETCH-LOGICAL-c546t-52f10aec6ba13d1dac54294b0687d17b8f979524a055e595856d73cd2b94bece3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/ng.3063$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/ng.3063$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25108383$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:129739039$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Geller, Frank</creatorcontrib><creatorcontrib>Feenstra, Bjarke</creatorcontrib><creatorcontrib>Carstensen, Lisbeth</creatorcontrib><creatorcontrib>Pers, Tune H</creatorcontrib><creatorcontrib>van Rooij, Iris A L M</creatorcontrib><creatorcontrib>Körberg, Izabella Baranowska</creatorcontrib><creatorcontrib>Choudhry, Shweta</creatorcontrib><creatorcontrib>Karjalainen, Juha M</creatorcontrib><creatorcontrib>Schnack, Tine H</creatorcontrib><creatorcontrib>Hollegaard, Mads V</creatorcontrib><creatorcontrib>Feitz, Wout F J</creatorcontrib><creatorcontrib>Roeleveld, Nel</creatorcontrib><creatorcontrib>Hougaard, David M</creatorcontrib><creatorcontrib>Hirschhorn, Joel N</creatorcontrib><creatorcontrib>Franke, Lude</creatorcontrib><creatorcontrib>Baskin, Laurence S</creatorcontrib><creatorcontrib>Nordenskjöld, Agneta</creatorcontrib><creatorcontrib>van der Zanden, Loes F M</creatorcontrib><creatorcontrib>Melbye, Mads</creatorcontrib><title>Genome-wide association analyses identify variants in developmental genes associated with hypospadias</title><title>Nature genetics</title><addtitle>Nat Genet</addtitle><addtitle>Nat Genet</addtitle><description>Frank Geller and colleagues report the results of a large genome-wide association study of hypospadias. They identify 18 susceptibility regions for this common congenital condition, many of which harbor genes important for embryonic development.
Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1,812 controls from Denmark, the Netherlands and Sweden, 18 genomic regions showed independent association with
P
< 5 × 10
−8
. Together, these loci explain 9% of the liability to developing this condition. Several of the identified regions harbor genes with key roles in embryonic development (including
HOXA4
,
IRX5
,
IRX6
and
EYA1
). Subsequent pathway analysis with GRAIL and DEPICT provided additional insight into possible genetic mechanisms causing hypospadias.</description><subject>45</subject><subject>45/43</subject><subject>45/88</subject><subject>631/208/205/2138</subject><subject>692/699/2768</subject><subject>Agriculture</subject><subject>Animal Genetics and Genomics</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Case-Control Studies</subject><subject>Councils</subject><subject>Denmark</subject><subject>Development and progression</subject><subject>Embryonic growth stage</subject><subject>Female</subject><subject>Gene Function</subject><subject>Genes</subject><subject>Genes, Developmental</subject><subject>Genetic aspects</subject><subject>Genetic Predisposition to Disease</subject><subject>Genome-wide association studies</subject><subject>Genome-Wide Association Study - methods</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Genotype</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Hypospadias</subject><subject>Hypospadias - genetics</subject><subject>Identification and classification</subject><subject>Male</subject><subject>Methods</subject><subject>Netherlands</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Quantitative trait loci</subject><subject>Studies</subject><subject>Sweden</subject><issn>1061-4036</issn><issn>1546-1718</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkk1v1DAQhi1ERcuC-AcoEofCIa0dx05yrCoolSpVgsLVmsST1CWxg5102X-Po922bE-cPJr38Xy8GkLeMXrCKC9PbXfCqeQvyBETuUxZwcqXMaaSpTnl8pC8DuGOUpbntHxFDjPBaMlLfkTwAq0bMF0bjQmE4BoDk3E2AQv9JmBIomAn026Se_AG7BQzNtF4j70bhyhBn3RoI_jwG3WyNtNtcrsZXRhBGwhvyEELfcC3u3dFfnz5fHP-Nb26vrg8P7tKmzj1lIqsZRSwkTUwrpmGmM6qvKayLDQr6rKtikpkOVAhUFSiFFIXvNFZHSFskK9Iuq0b1jjOtRq9GcBvlAOjdqlfMUIlWCWrKvIft_zo3e8Zw6QGExrse7Do5qCYiD1YVUWPV-TDM_TOzT6atFCSyoLuUR30qIxt3eShWYqqs-g3z8o8X9p-2qMaZyf8M3Uwh6Auv3_7f_b65z57vGUb70Lw2D4awKha7kTZTi13Esn3u23mekD9yD0cxpMzIUq2Q__Pus9q_QX9M8P8</recordid><startdate>20140901</startdate><enddate>20140901</enddate><creator>Geller, Frank</creator><creator>Feenstra, Bjarke</creator><creator>Carstensen, Lisbeth</creator><creator>Pers, Tune H</creator><creator>van Rooij, Iris A L M</creator><creator>Körberg, Izabella Baranowska</creator><creator>Choudhry, Shweta</creator><creator>Karjalainen, Juha M</creator><creator>Schnack, Tine H</creator><creator>Hollegaard, Mads V</creator><creator>Feitz, Wout F J</creator><creator>Roeleveld, Nel</creator><creator>Hougaard, David M</creator><creator>Hirschhorn, Joel N</creator><creator>Franke, Lude</creator><creator>Baskin, Laurence S</creator><creator>Nordenskjöld, Agneta</creator><creator>van der Zanden, Loes F M</creator><creator>Melbye, Mads</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>ADTPV</scope><scope>AOWAS</scope></search><sort><creationdate>20140901</creationdate><title>Genome-wide association analyses identify variants in developmental genes associated with hypospadias</title><author>Geller, Frank ; Feenstra, Bjarke ; Carstensen, Lisbeth ; Pers, Tune H ; van Rooij, Iris A L M ; Körberg, Izabella Baranowska ; Choudhry, Shweta ; Karjalainen, Juha M ; Schnack, Tine H ; Hollegaard, Mads V ; Feitz, Wout F J ; Roeleveld, Nel ; Hougaard, David M ; Hirschhorn, Joel N ; Franke, Lude ; Baskin, Laurence S ; Nordenskjöld, Agneta ; van der Zanden, Loes F M ; Melbye, Mads</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c546t-52f10aec6ba13d1dac54294b0687d17b8f979524a055e595856d73cd2b94bece3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>45</topic><topic>45/43</topic><topic>45/88</topic><topic>631/208/205/2138</topic><topic>692/699/2768</topic><topic>Agriculture</topic><topic>Animal Genetics and Genomics</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Case-Control Studies</topic><topic>Councils</topic><topic>Denmark</topic><topic>Development and progression</topic><topic>Embryonic growth stage</topic><topic>Female</topic><topic>Gene Function</topic><topic>Genes</topic><topic>Genes, Developmental</topic><topic>Genetic aspects</topic><topic>Genetic Predisposition to Disease</topic><topic>Genome-wide association studies</topic><topic>Genome-Wide Association Study - methods</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Genotype</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Hypospadias</topic><topic>Hypospadias - genetics</topic><topic>Identification and classification</topic><topic>Male</topic><topic>Methods</topic><topic>Netherlands</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Quantitative trait loci</topic><topic>Studies</topic><topic>Sweden</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Geller, Frank</creatorcontrib><creatorcontrib>Feenstra, Bjarke</creatorcontrib><creatorcontrib>Carstensen, Lisbeth</creatorcontrib><creatorcontrib>Pers, Tune H</creatorcontrib><creatorcontrib>van Rooij, Iris A L M</creatorcontrib><creatorcontrib>Körberg, Izabella Baranowska</creatorcontrib><creatorcontrib>Choudhry, Shweta</creatorcontrib><creatorcontrib>Karjalainen, Juha M</creatorcontrib><creatorcontrib>Schnack, Tine H</creatorcontrib><creatorcontrib>Hollegaard, Mads V</creatorcontrib><creatorcontrib>Feitz, Wout F J</creatorcontrib><creatorcontrib>Roeleveld, Nel</creatorcontrib><creatorcontrib>Hougaard, David M</creatorcontrib><creatorcontrib>Hirschhorn, Joel N</creatorcontrib><creatorcontrib>Franke, Lude</creatorcontrib><creatorcontrib>Baskin, Laurence S</creatorcontrib><creatorcontrib>Nordenskjöld, Agneta</creatorcontrib><creatorcontrib>van der Zanden, Loes F M</creatorcontrib><creatorcontrib>Melbye, Mads</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</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>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research 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>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</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>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</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>Research Library</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</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 Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>SwePub</collection><collection>SwePub Articles</collection><jtitle>Nature genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Geller, Frank</au><au>Feenstra, Bjarke</au><au>Carstensen, Lisbeth</au><au>Pers, Tune H</au><au>van Rooij, Iris A L M</au><au>Körberg, Izabella Baranowska</au><au>Choudhry, Shweta</au><au>Karjalainen, Juha M</au><au>Schnack, Tine H</au><au>Hollegaard, Mads V</au><au>Feitz, Wout F J</au><au>Roeleveld, Nel</au><au>Hougaard, David M</au><au>Hirschhorn, Joel N</au><au>Franke, Lude</au><au>Baskin, Laurence S</au><au>Nordenskjöld, Agneta</au><au>van der Zanden, Loes F M</au><au>Melbye, Mads</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome-wide association analyses identify variants in developmental genes associated with hypospadias</atitle><jtitle>Nature genetics</jtitle><stitle>Nat Genet</stitle><addtitle>Nat Genet</addtitle><date>2014-09-01</date><risdate>2014</risdate><volume>46</volume><issue>9</issue><spage>957</spage><epage>963</epage><pages>957-963</pages><issn>1061-4036</issn><eissn>1546-1718</eissn><abstract>Frank Geller and colleagues report the results of a large genome-wide association study of hypospadias. They identify 18 susceptibility regions for this common congenital condition, many of which harbor genes important for embryonic development.
Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1,812 controls from Denmark, the Netherlands and Sweden, 18 genomic regions showed independent association with
P
< 5 × 10
−8
. Together, these loci explain 9% of the liability to developing this condition. Several of the identified regions harbor genes with key roles in embryonic development (including
HOXA4
,
IRX5
,
IRX6
and
EYA1
). Subsequent pathway analysis with GRAIL and DEPICT provided additional insight into possible genetic mechanisms causing hypospadias.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25108383</pmid><doi>10.1038/ng.3063</doi><tpages>7</tpages></addata></record> |
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subjects | 45 45/43 45/88 631/208/205/2138 692/699/2768 Agriculture Animal Genetics and Genomics Biomedicine Cancer Research Case-Control Studies Councils Denmark Development and progression Embryonic growth stage Female Gene Function Genes Genes, Developmental Genetic aspects Genetic Predisposition to Disease Genome-wide association studies Genome-Wide Association Study - methods Genomes Genomics Genotype Human Genetics Humans Hypospadias Hypospadias - genetics Identification and classification Male Methods Netherlands Polymorphism, Single Nucleotide Quantitative trait loci Studies Sweden |
title | Genome-wide association analyses identify variants in developmental genes associated with hypospadias |
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