Multiple regions of α‐synuclein are associated with Parkinson's disease
Identifieur interne : 002122 ( Main/Corpus ); précédent : 002121; suivant : 002123Multiple regions of α‐synuclein are associated with Parkinson's disease
Auteurs : Jakob C. Mueller ; Julia Fuchs ; Anne Hofer ; Alexander Zimprich ; Peter Lichtner ; Thomas Illig ; Daniela Berg ; Ullrich Wüllner ; Thomas Meitinger ; Thomas GasserSource :
- Annals of Neurology [ 0364-5134 ] ; 2005-04.
Abstract
α‐Synuclein is considered to play an important role in the pathogenesis of both the rare familial and the common sporadic forms of Parkinson's disease. Previous reports primarily have tested the association of α‐synuclein promoter polymorphisms with idiopathic Parkinson's disease, but results are controversial. We first characterized the linkage disequilibrium structure of the α‐synuclein gene region with a dense set of 56 genetic markers and subsequently performed two independent case–control association analyses using tagging markers. We could distinguish two large linkage disequilibrium blocks spanning the α‐synuclein gene. Several markers within the 3′‐block around exons 5 and 6 showed strong association with Parkinson's disease (p = 0.00009). Effects of the associated variants might be mediated by regulatory elements in this highly conserved region or by a frequency shift in a previously described splice variant lacking exon 5. A direct association with promoter polymorphisms could not be replicated in our sample set. A second set of markers in the 5′‐block of the gene were also significantly associated with Parkinson's disease, when young patients and female subjects were analyzed separately. These findings indicate locus heterogeneity for the pathogenesis of Parkinson's disease in different genetic or physiological environments, related to sex and age. Ann Neurol 2005;57:535–541
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DOI: 10.1002/ana.20438
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Previous reports primarily have tested the association of α‐synuclein promoter polymorphisms with idiopathic Parkinson's disease, but results are controversial. We first characterized the linkage disequilibrium structure of the α‐synuclein gene region with a dense set of 56 genetic markers and subsequently performed two independent case–control association analyses using tagging markers. We could distinguish two large linkage disequilibrium blocks spanning the α‐synuclein gene. Several markers within the 3′‐block around exons 5 and 6 showed strong association with Parkinson's disease (p = 0.00009). Effects of the associated variants might be mediated by regulatory elements in this highly conserved region or by a frequency shift in a previously described splice variant lacking exon 5. A direct association with promoter polymorphisms could not be replicated in our sample set. A second set of markers in the 5′‐block of the gene were also significantly associated with Parkinson's disease, when young patients and female subjects were analyzed separately. These findings indicate locus heterogeneity for the pathogenesis of Parkinson's disease in different genetic or physiological environments, related to sex and age. Ann Neurol 2005;57:535–541</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Jakob C. Mueller PhD</name><affiliations><json:string>Institute for Human Genetics, GSF–National Research Centre for Environment and Health, Neuherberg, Germany</json:string></affiliations></json:item><json:item><name>Julia Fuchs MD</name><affiliations><json:string>Department for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</json:string></affiliations></json:item><json:item><name>Anne Hofer MD</name><affiliations><json:string>Department for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</json:string></affiliations></json:item><json:item><name>Alexander Zimprich MD</name><affiliations><json:string>Department of Neurology, AKH, University of Vienna, Vienna, Austria</json:string></affiliations></json:item><json:item><name>Peter Lichtner PhD</name><affiliations><json:string>Institute for Human Genetics, GSF–National Research Centre for Environment and Health, Neuherberg, Germany</json:string></affiliations></json:item><json:item><name>Thomas Illig PhD</name><affiliations><json:string>Institute for Epidemiology, GSF–National Research Centre for Environment and Health, Neuherberg, Germany</json:string></affiliations></json:item><json:item><name>Daniela Berg MD</name><affiliations><json:string>Department for Medical Genetics, Hertie‐Institute for Clinical Brain Research, Tübingen, Germany</json:string></affiliations></json:item><json:item><name>Ullrich Wüllner MD</name><affiliations><json:string>Department of Neurology, University of Bonn, Bonn, Germany</json:string></affiliations></json:item><json:item><name>Thomas Meitinger PhD</name><affiliations><json:string>Institute for Human Genetics, GSF–National Research Centre for Environment and Health, Neuherberg, Germany</json:string></affiliations></json:item><json:item><name>Thomas Gasser MD</name><affiliations><json:string>Department for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</json:string></affiliations></json:item></author><articleId><json:string>ANA20438</json:string></articleId><language><json:string>eng</json:string></language><abstract>α‐Synuclein is considered to play an important role in the pathogenesis of both the rare familial and the common sporadic forms of Parkinson's disease. Previous reports primarily have tested the association of α‐synuclein promoter polymorphisms with idiopathic Parkinson's disease, but results are controversial. We first characterized the linkage disequilibrium structure of the α‐synuclein gene region with a dense set of 56 genetic markers and subsequently performed two independent case–control association analyses using tagging markers. We could distinguish two large linkage disequilibrium blocks spanning the α‐synuclein gene. Several markers within the 3′‐block around exons 5 and 6 showed strong association with Parkinson's disease (p = 0.00009). Effects of the associated variants might be mediated by regulatory elements in this highly conserved region or by a frequency shift in a previously described splice variant lacking exon 5. A direct association with promoter polymorphisms could not be replicated in our sample set. A second set of markers in the 5′‐block of the gene were also significantly associated with Parkinson's disease, when young patients and female subjects were analyzed separately. These findings indicate locus heterogeneity for the pathogenesis of Parkinson's disease in different genetic or physiological environments, related to sex and age. 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No. 031U112C;</note><note>German National Genome Network (German Ministry for Education and Research) - No. 01GS0116;</note><note>Udall Center of Excellence in Parkinson's disease (NIH) - No. NS40256;</note><note>Competence Network Parkinson's disease (German Ministry for Education and Research) - No. 01Gl0201;</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Multiple regions of α‐synuclein are associated with Parkinson's disease</title><author><persName><forename type="first">Jakob C.</forename><surname>Mueller</surname></persName><roleName type="degree">PhD</roleName><affiliation>Institute for Human Genetics, GSF–National Research Centre for Environment and Health, Neuherberg, Germany</affiliation></author><author><persName><forename type="first">Julia</forename><surname>Fuchs</surname></persName><roleName type="degree">MD</roleName><affiliation>Department for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation></author><author><persName><forename type="first">Anne</forename><surname>Hofer</surname></persName><roleName type="degree">MD</roleName><affiliation>Department for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation></author><author><persName><forename type="first">Alexander</forename><surname>Zimprich</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, AKH, University of Vienna, Vienna, Austria</affiliation></author><author><persName><forename type="first">Peter</forename><surname>Lichtner</surname></persName><roleName type="degree">PhD</roleName><affiliation>Institute for Human Genetics, GSF–National Research Centre for Environment and Health, Neuherberg, Germany</affiliation></author><author><persName><forename type="first">Thomas</forename><surname>Illig</surname></persName><roleName type="degree">PhD</roleName><affiliation>Institute for Epidemiology, GSF–National Research Centre for Environment and Health, Neuherberg, Germany</affiliation></author><author><persName><forename type="first">Daniela</forename><surname>Berg</surname></persName><roleName type="degree">MD</roleName><affiliation>Department for Medical Genetics, Hertie‐Institute for Clinical Brain Research, Tübingen, Germany</affiliation></author><author><persName><forename type="first">Ullrich</forename><surname>Wüllner</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, University of Bonn, Bonn, Germany</affiliation></author><author><persName><forename type="first">Thomas</forename><surname>Meitinger</surname></persName><roleName type="degree">PhD</roleName><affiliation>Institute for Human Genetics, GSF–National Research Centre for Environment and Health, Neuherberg, Germany</affiliation></author><author><persName><forename type="first">Thomas</forename><surname>Gasser</surname></persName><roleName type="degree">MD</roleName><note type="correspondence"><p>Correspondence: Hertie‐Institute for Clinical Brain Research, Department for Neurodegenerative Diseases, University of Tübingen, Otfried‐Müller‐Strasse 27, 72076 Tübingen, Germany</p></note><affiliation>Department for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation></author></analytic><monogr><title level="j">Annals of Neurology</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="pISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><idno type="DOI">10.1002/(ISSN)1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2005-04"></date><biblScope unit="volume">57</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="535">535</biblScope><biblScope unit="page" to="541">541</biblScope></imprint></monogr><idno type="istex">B5631BC42A7F6873BB6F2CCF2D55C96B83E1C69E</idno><idno type="DOI">10.1002/ana.20438</idno><idno type="ArticleID">ANA20438</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2005</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>α‐Synuclein is considered to play an important role in the pathogenesis of both the rare familial and the common sporadic forms of Parkinson's disease. Previous reports primarily have tested the association of α‐synuclein promoter polymorphisms with idiopathic Parkinson's disease, but results are controversial. We first characterized the linkage disequilibrium structure of the α‐synuclein gene region with a dense set of 56 genetic markers and subsequently performed two independent case–control association analyses using tagging markers. We could distinguish two large linkage disequilibrium blocks spanning the α‐synuclein gene. Several markers within the 3′‐block around exons 5 and 6 showed strong association with Parkinson's disease (p = 0.00009). Effects of the associated variants might be mediated by regulatory elements in this highly conserved region or by a frequency shift in a previously described splice variant lacking exon 5. A direct association with promoter polymorphisms could not be replicated in our sample set. A second set of markers in the 5′‐block of the gene were also significantly associated with Parkinson's disease, when young patients and female subjects were analyzed separately. These findings indicate locus heterogeneity for the pathogenesis of Parkinson's disease in different genetic or physiological environments, related to sex and age. 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affiliationRef="#af4"><personName><givenNames>Thomas</givenNames><familyName>Illig</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af5"><personName><givenNames>Daniela</givenNames><familyName>Berg</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af6"><personName><givenNames>Ullrich</givenNames><familyName>Wüllner</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Thomas</givenNames><familyName>Meitinger</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af2" corresponding="yes"><personName><givenNames>Thomas</givenNames><familyName>Gasser</familyName><degrees>MD</degrees></personName><contactDetails><email normalForm="thomas.gasser@med.uni-tuebingen.de">thomas.gasser@med.uni‐tuebingen.de</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="DE" type="organization"><unparsedAffiliation>Institute for Human Genetics, GSF–National Research Centre for Environment and Health, Neuherberg, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="DE" type="organization"><unparsedAffiliation>Department for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="AT" type="organization"><unparsedAffiliation>Department of Neurology, AKH, University of Vienna, Vienna, Austria</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="DE" type="organization"><unparsedAffiliation>Institute for Epidemiology, GSF–National Research Centre for Environment and Health, Neuherberg, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af5" countryCode="DE" type="organization"><unparsedAffiliation>Department for Medical Genetics, Hertie‐Institute for Clinical Brain Research, Tübingen, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af6" countryCode="DE" type="organization"><unparsedAffiliation>Department of Neurology, University of Bonn, Bonn, Germany</unparsedAffiliation></affiliation></affiliationGroup><fundingInfo><fundingAgency>German Federal Ministry of Education and Research</fundingAgency><fundingNumber>031U112C</fundingNumber></fundingInfo><fundingInfo><fundingAgency>German National Genome Network (German Ministry for Education and Research)</fundingAgency><fundingNumber>01GS0116</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Udall Center of Excellence in Parkinson's disease (NIH)</fundingAgency><fundingNumber>NS40256</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Competence Network Parkinson's disease (German Ministry for Education and Research)</fundingAgency><fundingNumber>01Gl0201</fundingNumber></fundingInfo><supportingInformation><p> This article includes supplementary materials available via the Internet at <url href="http://www.interscience.wiley.com/jpages/0364-5134/suppmat"> http://www.interscience.wiley.com/jpages/0364‐5134/suppmat </url></p><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:03645134:media:ana20438:jws-ana"></mediaResource><caption>Supplementary Table 1.</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>α‐Synuclein is considered to play an important role in the pathogenesis of both the rare familial and the common sporadic forms of Parkinson's disease. Previous reports primarily have tested the association of α‐synuclein promoter polymorphisms with idiopathic Parkinson's disease, but results are controversial. We first characterized the linkage disequilibrium structure of the α‐synuclein gene region with a dense set of 56 genetic markers and subsequently performed two independent case–control association analyses using tagging markers. We could distinguish two large linkage disequilibrium blocks spanning the α‐synuclein gene. Several markers within the 3′‐block around exons 5 and 6 showed strong association with Parkinson's disease (<i>p</i> = 0.00009). Effects of the associated variants might be mediated by regulatory elements in this highly conserved region or by a frequency shift in a previously described splice variant lacking exon 5. A direct association with promoter polymorphisms could not be replicated in our sample set. A second set of markers in the 5′‐block of the gene were also significantly associated with Parkinson's disease, when young patients and female subjects were analyzed separately. These findings indicate locus heterogeneity for the pathogenesis of Parkinson's disease in different genetic or physiological environments, related to sex and age. Ann Neurol 2005;57:535–541</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Multiple regions of α‐synuclein are associated with Parkinson's disease</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Multiple SNCA Associations in PD</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Multiple regions of α‐synuclein are associated with Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Jakob C.</namePart><namePart type="family">Mueller</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Institute for Human Genetics, GSF–National Research Centre for Environment and Health, Neuherberg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Julia</namePart><namePart type="family">Fuchs</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Anne</namePart><namePart type="family">Hofer</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alexander</namePart><namePart type="family">Zimprich</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, AKH, University of Vienna, Vienna, Austria</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">Lichtner</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Institute for Human Genetics, GSF–National Research Centre for Environment and Health, Neuherberg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas</namePart><namePart type="family">Illig</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Institute for Epidemiology, GSF–National Research Centre for Environment and Health, Neuherberg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Daniela</namePart><namePart type="family">Berg</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department for Medical Genetics, Hertie‐Institute for Clinical Brain Research, Tübingen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ullrich</namePart><namePart type="family">Wüllner</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of Bonn, Bonn, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas</namePart><namePart type="family">Meitinger</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Institute for Human Genetics, GSF–National Research Centre for Environment and Health, Neuherberg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas</namePart><namePart type="family">Gasser</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation><description>Correspondence: Hertie‐Institute for Clinical Brain Research, Department for Neurodegenerative Diseases, University of Tübingen, Otfried‐Müller‐Strasse 27, 72076 Tübingen, Germany</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2005-04</dateIssued><dateCaptured encoding="w3cdtf">2004-11-05</dateCaptured><dateValid encoding="w3cdtf">2005-01-28</dateValid><copyrightDate encoding="w3cdtf">2005</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">1</extent><extent unit="tables">2</extent><extent unit="references">32</extent><extent unit="words">4361</extent></physicalDescription><abstract lang="en">α‐Synuclein is considered to play an important role in the pathogenesis of both the rare familial and the common sporadic forms of Parkinson's disease. Previous reports primarily have tested the association of α‐synuclein promoter polymorphisms with idiopathic Parkinson's disease, but results are controversial. We first characterized the linkage disequilibrium structure of the α‐synuclein gene region with a dense set of 56 genetic markers and subsequently performed two independent case–control association analyses using tagging markers. We could distinguish two large linkage disequilibrium blocks spanning the α‐synuclein gene. Several markers within the 3′‐block around exons 5 and 6 showed strong association with Parkinson's disease (p = 0.00009). Effects of the associated variants might be mediated by regulatory elements in this highly conserved region or by a frequency shift in a previously described splice variant lacking exon 5. A direct association with promoter polymorphisms could not be replicated in our sample set. A second set of markers in the 5′‐block of the gene were also significantly associated with Parkinson's disease, when young patients and female subjects were analyzed separately. These findings indicate locus heterogeneity for the pathogenesis of Parkinson's disease in different genetic or physiological environments, related to sex and age. Ann Neurol 2005;57:535–541</abstract><note type="funding">German Federal Ministry of Education and Research - No. 031U112C; </note><note type="funding">German National Genome Network (German Ministry for Education and Research) - No. 01GS0116; </note><note type="funding">Udall Center of Excellence in Parkinson's disease (NIH) - No. NS40256; </note><note type="funding">Competence Network Parkinson's disease (German Ministry for Education and Research) - No. 01Gl0201; </note><relatedItem type="host"><titleInfo><title>Annals of Neurology</title></titleInfo><titleInfo type="abbreviated"><title>Ann Neurol.</title></titleInfo><genre type="Journal">journal</genre><note type="content"> This article includes supplementary materials available via the Internet at http://www.interscience.wiley.com/jpages/0364‐5134/suppmatSupporting Info Item: Supplementary Table 1. - </note><subject><genre>article category</genre><topic>Original Article</topic></subject><identifier type="ISSN">0364-5134</identifier><identifier type="eISSN">1531-8249</identifier><identifier type="DOI">10.1002/(ISSN)1531-8249</identifier><identifier type="PublisherID">ANA</identifier><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>57</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>535</start><end>541</end><total>7</total></extent></part></relatedItem><identifier type="istex">B5631BC42A7F6873BB6F2CCF2D55C96B83E1C69E</identifier><identifier type="DOI">10.1002/ana.20438</identifier><identifier type="ArticleID">ANA20438</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2005 American Neurological Association</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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