Multiple candidate gene analysis identifies α-synuclein as a susceptibility gene for sporadic Parkinson's disease
Identifieur interne : 000590 ( Main/Corpus ); précédent : 000589; suivant : 000591Multiple candidate gene analysis identifies α-synuclein as a susceptibility gene for sporadic Parkinson's disease
Auteurs : Ikuko Mizuta ; Wataru Satake ; Yuko Nakabayashi ; Chiyomi Ito ; Satoko Suzuki ; Yoshio Momose ; Yoshitaka Nagai ; Akira Oka ; Hidetoshi Inoko ; Jiro Fukae ; Yuko Saito ; Motoji Sawabe ; Shigeo Murayama ; Mitsutoshi Yamamoto ; Nobutaka Hattori ; Miho Murata ; Tatsushi TodaSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2006-04-01.
Abstract
Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. PD is a complex disorder with multiple genetic and environmental factors influencing disease risk. To identify susceptible genes for sporadic PD, we performed case–control association studies of 268 single nucleotide polymorphisms (SNPs) in 121 candidate genes. In two independent case–control populations, we found that a SNP in α-synuclein (SNCA), rs7684318, showed the strongest association with PD (P=5.0×10−10). Linkage disequilibrium (LD) analysis using 29 SNPs in a region around rs7684318 revealed that the entire SNCA gene lies within a single LD block (D′>0.9) spanning ∼120 kb. A tight LD group (r2>0.85) of six SNPs, including rs7684318, associated most strongly with PD (P=2.0×10−9–1.7×10−11). Haplotype association analysis did not show lower P-values than any single SNP within this group. SNCA is a major component of Lewy bodies, the pathological hallmark of PD. Aggregation of SNCA is thought to play a crucial role in PD. SNCA expression levels tended to be positively correlated with the number of the associated allele in autopsied frontal cortices. These findings establish SNCA as a definite susceptibility gene for sporadic PD.
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DOI: 10.1093/hmg/ddl030
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Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Nakabayashi, Yuko" sort="Nakabayashi, Yuko" uniqKey="Nakabayashi Y" first="Yuko" last="Nakabayashi">Yuko Nakabayashi</name><affiliation><mods:affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</mods:affiliation></affiliation><affiliation><mods:affiliation>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Ito, Chiyomi" sort="Ito, Chiyomi" uniqKey="Ito C" first="Chiyomi" last="Ito">Chiyomi Ito</name><affiliation><mods:affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</mods:affiliation></affiliation><affiliation><mods:affiliation>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Suzuki, Satoko" sort="Suzuki, Satoko" uniqKey="Suzuki S" first="Satoko" last="Suzuki">Satoko Suzuki</name><affiliation><mods:affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</mods:affiliation></affiliation><affiliation><mods:affiliation>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Momose, Yoshio" sort="Momose, Yoshio" uniqKey="Momose Y" first="Yoshio" last="Momose">Yoshio Momose</name><affiliation><mods:affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Nagai, Yoshitaka" sort="Nagai, Yoshitaka" uniqKey="Nagai Y" first="Yoshitaka" last="Nagai">Yoshitaka Nagai</name><affiliation><mods:affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Oka, Akira" sort="Oka, Akira" uniqKey="Oka A" first="Akira" last="Oka">Akira Oka</name><affiliation><mods:affiliation>Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 259-1193, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Inoko, Hidetoshi" sort="Inoko, Hidetoshi" uniqKey="Inoko H" first="Hidetoshi" last="Inoko">Hidetoshi Inoko</name><affiliation><mods:affiliation>Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 259-1193, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Fukae, Jiro" sort="Fukae, Jiro" uniqKey="Fukae J" first="Jiro" last="Fukae">Jiro Fukae</name><affiliation><mods:affiliation>Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Saito, Yuko" sort="Saito, Yuko" uniqKey="Saito Y" first="Yuko" last="Saito">Yuko Saito</name><affiliation><mods:affiliation>Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Sawabe, Motoji" sort="Sawabe, Motoji" uniqKey="Sawabe M" first="Motoji" last="Sawabe">Motoji Sawabe</name><affiliation><mods:affiliation>Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Murayama, Shigeo" sort="Murayama, Shigeo" uniqKey="Murayama S" first="Shigeo" last="Murayama">Shigeo Murayama</name><affiliation><mods:affiliation>Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Yamamoto, Mitsutoshi" sort="Yamamoto, Mitsutoshi" uniqKey="Yamamoto M" first="Mitsutoshi" last="Yamamoto">Mitsutoshi Yamamoto</name><affiliation><mods:affiliation>Department of Neurology, Kagawa Prefectural Central Hospital, Takamatsu 760-8557, Japan and</mods:affiliation></affiliation></author><author><name sortKey="Hattori, Nobutaka" sort="Hattori, Nobutaka" uniqKey="Hattori N" first="Nobutaka" last="Hattori">Nobutaka Hattori</name><affiliation><mods:affiliation>Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Murata, Miho" sort="Murata, Miho" uniqKey="Murata M" first="Miho" last="Murata">Miho Murata</name><affiliation><mods:affiliation>Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan</mods:affiliation></affiliation></author><author><name sortKey="Toda, Tatsushi" sort="Toda, Tatsushi" uniqKey="Toda T" first="Tatsushi" last="Toda">Tatsushi Toda</name><affiliation><mods:affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</mods:affiliation></affiliation><affiliation><mods:affiliation>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: toda@clgene.med.osaka-u.ac.jp</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><title level="j" type="abbrev">Hum. Mol. Genet.</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2006-04-01">2006-04-01</date><biblScope unit="volume">15</biblScope><biblScope unit="issue">7</biblScope><biblScope unit="page" from="1151">1151</biblScope><biblScope unit="page" to="1158">1158</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">D66103F44B7C0A027672E53C0AC8CA54EFD09265</idno><idno type="DOI">10.1093/hmg/ddl030</idno><idno type="href">ddl030</idno><idno type="local">ddl030</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. PD is a complex disorder with multiple genetic and environmental factors influencing disease risk. To identify susceptible genes for sporadic PD, we performed case–control association studies of 268 single nucleotide polymorphisms (SNPs) in 121 candidate genes. In two independent case–control populations, we found that a SNP in α-synuclein (SNCA), rs7684318, showed the strongest association with PD (P=5.0×10−10). Linkage disequilibrium (LD) analysis using 29 SNPs in a region around rs7684318 revealed that the entire SNCA gene lies within a single LD block (D′>0.9) spanning ∼120 kb. A tight LD group (r2>0.85) of six SNPs, including rs7684318, associated most strongly with PD (P=2.0×10−9–1.7×10−11). Haplotype association analysis did not show lower P-values than any single SNP within this group. SNCA is a major component of Lewy bodies, the pathological hallmark of PD. Aggregation of SNCA is thought to play a crucial role in PD. SNCA expression levels tended to be positively correlated with the number of the associated allele in autopsied frontal cortices. These findings establish SNCA as a definite susceptibility gene for sporadic PD.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Ikuko Mizuta</name><affiliations><json:string>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</json:string></affiliations></json:item><json:item><name>Wataru Satake</name><affiliations><json:string>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</json:string></affiliations></json:item><json:item><name>Yuko Nakabayashi</name><affiliations><json:string>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</json:string><json:string>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</json:string></affiliations></json:item><json:item><name>Chiyomi Ito</name><affiliations><json:string>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</json:string><json:string>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</json:string></affiliations></json:item><json:item><name>Satoko Suzuki</name><affiliations><json:string>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</json:string><json:string>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</json:string></affiliations></json:item><json:item><name>Yoshio Momose</name><affiliations><json:string>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</json:string></affiliations></json:item><json:item><name>Yoshitaka Nagai</name><affiliations><json:string>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</json:string></affiliations></json:item><json:item><name>Akira Oka</name><affiliations><json:string>Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 259-1193, Japan,</json:string></affiliations></json:item><json:item><name>Hidetoshi Inoko</name><affiliations><json:string>Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 259-1193, Japan,</json:string></affiliations></json:item><json:item><name>Jiro Fukae</name><affiliations><json:string>Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan,</json:string></affiliations></json:item><json:item><name>Yuko Saito</name><affiliations><json:string>Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan,</json:string><json:string>Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan,</json:string></affiliations></json:item><json:item><name>Motoji Sawabe</name><affiliations><json:string>Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan,</json:string></affiliations></json:item><json:item><name>Shigeo Murayama</name><affiliations><json:string>Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan,</json:string></affiliations></json:item><json:item><name>Mitsutoshi Yamamoto</name><affiliations><json:string>Department of Neurology, Kagawa Prefectural Central Hospital, Takamatsu 760-8557, Japan and</json:string></affiliations></json:item><json:item><name>Nobutaka Hattori</name><affiliations><json:string>Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan,</json:string></affiliations></json:item><json:item><name>Miho Murata</name><affiliations><json:string>Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan</json:string></affiliations></json:item><json:item><name>Tatsushi Toda</name><affiliations><json:string>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</json:string><json:string>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</json:string><json:string>E-mail: toda@clgene.med.osaka-u.ac.jp</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>ARTICLES</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. PD is a complex disorder with multiple genetic and environmental factors influencing disease risk. To identify susceptible genes for sporadic PD, we performed case–control association studies of 268 single nucleotide polymorphisms (SNPs) in 121 candidate genes. In two independent case–control populations, we found that a SNP in α-synuclein (SNCA), rs7684318, showed the strongest association with PD (P=5.0×10−10). Linkage disequilibrium (LD) analysis using 29 SNPs in a region around rs7684318 revealed that the entire SNCA gene lies within a single LD block (D′>0.9) spanning ∼120 kb. A tight LD group (r2>0.85) of six SNPs, including rs7684318, associated most strongly with PD (P=2.0×10−9–1.7×10−11). Haplotype association analysis did not show lower P-values than any single SNP within this group. SNCA is a major component of Lewy bodies, the pathological hallmark of PD. Aggregation of SNCA is thought to play a crucial role in PD. SNCA expression levels tended to be positively correlated with the number of the associated allele in autopsied frontal cortices. These findings establish SNCA as a definite susceptibility gene for sporadic PD.</abstract><qualityIndicators><score>7.364</score><pdfVersion>1.3</pdfVersion><pdfPageSize>610 x 795 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>1</keywordCount><abstractCharCount>1328</abstractCharCount><pdfWordCount>5020</pdfWordCount><pdfCharCount>33552</pdfCharCount><pdfPageCount>8</pdfPageCount><abstractWordCount>197</abstractWordCount></qualityIndicators><title>Multiple candidate gene analysis identifies α-synuclein as a susceptibility gene for sporadic Parkinson's disease</title><genre><json:string>research-article</json:string></genre><host><volume>15</volume><pages><last>1158</last><first>1151</first></pages><issn><json:string>0964-6906</json:string></issn><issue>7</issue><genre></genre><language><json:string>unknown</json:string></language><eissn><json:string>1460-2083</json:string></eissn><title>Human Molecular Genetics</title></host><categories><wos><json:string>BIOCHEMISTRY & MOLECULAR BIOLOGY</json:string><json:string>GENETICS & HEREDITY</json:string></wos></categories><publicationDate>2006</publicationDate><copyrightDate>2006</copyrightDate><doi><json:string>10.1093/hmg/ddl030</json:string></doi><id>D66103F44B7C0A027672E53C0AC8CA54EFD09265</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/D66103F44B7C0A027672E53C0AC8CA54EFD09265/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/D66103F44B7C0A027672E53C0AC8CA54EFD09265/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/D66103F44B7C0A027672E53C0AC8CA54EFD09265/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Multiple candidate gene analysis identifies α-synuclein as a susceptibility gene for sporadic Parkinson's disease</title><respStmt xml:id="ISTEX-API" resp="Références bibliographiques récupérées via GROBID" name="ISTEX-API (INIST-CNRS)"></respStmt></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>OUP</p></availability><date>2006-02-24</date></publicationStmt><notesStmt><note>*To whom correspondence should be addressed. Tel: +81 668793380; Fax: +81 668793389; Email: toda@clgene.med.osaka-u.ac.jp</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Multiple candidate gene analysis identifies α-synuclein as a susceptibility gene for sporadic Parkinson's disease</title><author><persName><forename type="first">Ikuko</forename><surname>Mizuta</surname></persName><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation></author><author><persName><forename type="first">Wataru</forename><surname>Satake</surname></persName><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation></author><author><persName><forename type="first">Yuko</forename><surname>Nakabayashi</surname></persName><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation><affiliation>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</affiliation></author><author><persName><forename type="first">Chiyomi</forename><surname>Ito</surname></persName><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation><affiliation>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</affiliation></author><author><persName><forename type="first">Satoko</forename><surname>Suzuki</surname></persName><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation><affiliation>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</affiliation></author><author><persName><forename type="first">Yoshio</forename><surname>Momose</surname></persName><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation></author><author><persName><forename type="first">Yoshitaka</forename><surname>Nagai</surname></persName><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation></author><author><persName><forename type="first">Akira</forename><surname>Oka</surname></persName><affiliation>Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 259-1193, Japan,</affiliation></author><author><persName><forename type="first">Hidetoshi</forename><surname>Inoko</surname></persName><affiliation>Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 259-1193, Japan,</affiliation></author><author><persName><forename type="first">Jiro</forename><surname>Fukae</surname></persName><affiliation>Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan,</affiliation></author><author><persName><forename type="first">Yuko</forename><surname>Saito</surname></persName><affiliation>Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan,</affiliation><affiliation>Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan,</affiliation></author><author><persName><forename type="first">Motoji</forename><surname>Sawabe</surname></persName><affiliation>Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan,</affiliation></author><author><persName><forename type="first">Shigeo</forename><surname>Murayama</surname></persName><affiliation>Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan,</affiliation></author><author><persName><forename type="first">Mitsutoshi</forename><surname>Yamamoto</surname></persName><affiliation>Department of Neurology, Kagawa Prefectural Central Hospital, Takamatsu 760-8557, Japan and</affiliation></author><author><persName><forename type="first">Nobutaka</forename><surname>Hattori</surname></persName><affiliation>Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan,</affiliation></author><author><persName><forename type="first">Miho</forename><surname>Murata</surname></persName><affiliation>Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan</affiliation></author><author><persName><forename type="first">Tatsushi</forename><surname>Toda</surname></persName><email>toda@clgene.med.osaka-u.ac.jp</email><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation><affiliation>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</affiliation></author></analytic><monogr><title level="j">Human Molecular Genetics</title><title level="j" type="abbrev">Hum. Mol. Genet.</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2006-04-01"></date><biblScope unit="volume">15</biblScope><biblScope unit="issue">7</biblScope><biblScope unit="page" from="1151">1151</biblScope><biblScope unit="page" to="1158">1158</biblScope></imprint></monogr><idno type="istex">D66103F44B7C0A027672E53C0AC8CA54EFD09265</idno><idno type="DOI">10.1093/hmg/ddl030</idno><idno type="href">ddl030</idno><idno type="local">ddl030</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2006-02-24</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. PD is a complex disorder with multiple genetic and environmental factors influencing disease risk. To identify susceptible genes for sporadic PD, we performed case–control association studies of 268 single nucleotide polymorphisms (SNPs) in 121 candidate genes. In two independent case–control populations, we found that a SNP in α-synuclein (SNCA), rs7684318, showed the strongest association with PD (P=5.0×10−10). Linkage disequilibrium (LD) analysis using 29 SNPs in a region around rs7684318 revealed that the entire SNCA gene lies within a single LD block (D′>0.9) spanning ∼120 kb. A tight LD group (r2>0.85) of six SNPs, including rs7684318, associated most strongly with PD (P=2.0×10−9–1.7×10−11). Haplotype association analysis did not show lower P-values than any single SNP within this group. SNCA is a major component of Lewy bodies, the pathological hallmark of PD. Aggregation of SNCA is thought to play a crucial role in PD. SNCA expression levels tended to be positively correlated with the number of the associated allele in autopsied frontal cortices. These findings establish SNCA as a definite susceptibility gene for sporadic PD.</p></abstract></profileDesc><revisionDesc><change when="2006-02-24">Created</change><change when="2006-04-01">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-3-15">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/D66103F44B7C0A027672E53C0AC8CA54EFD09265/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="US-ASCII"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article xml:lang="en" article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">hmg</journal-id><journal-id journal-id-type="nlm-ta">Hum Mol Genet</journal-id><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><abbrev-journal-title abbrev-type="publisher">Hum. Mol. Genet.</abbrev-journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="other">ddl030</article-id><article-id pub-id-type="doi">10.1093/hmg/ddl030</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Multiple candidate gene analysis identifies α-<italic>synuclein</italic> as a susceptibility gene for sporadic Parkinson's disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Mizuta</surname><given-names>Ikuko</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Satake</surname><given-names>Wataru</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Nakabayashi</surname><given-names>Yuko</given-names></name><xref rid="AF1">1</xref><xref rid="AF2">2</xref></contrib><contrib contrib-type="author"><name><surname>Ito</surname><given-names>Chiyomi</given-names></name><xref rid="AF1">1</xref><xref rid="AF2">2</xref></contrib><contrib contrib-type="author"><name><surname>Suzuki</surname><given-names>Satoko</given-names></name><xref rid="AF1">1</xref><xref rid="AF2">2</xref></contrib><contrib contrib-type="author"><name><surname>Momose</surname><given-names>Yoshio</given-names></name><xref rid="AF1">1</xref><xref rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Nagai</surname><given-names>Yoshitaka</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Oka</surname><given-names>Akira</given-names></name><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Inoko</surname><given-names>Hidetoshi</given-names></name><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Fukae</surname><given-names>Jiro</given-names></name><xref rid="AF4">4</xref></contrib><contrib contrib-type="author"><name><surname>Saito</surname><given-names>Yuko</given-names></name><xref rid="AF5">5</xref><xref rid="AF6">6</xref></contrib><contrib contrib-type="author"><name><surname>Sawabe</surname><given-names>Motoji</given-names></name><xref rid="AF5">5</xref></contrib><contrib contrib-type="author"><name><surname>Murayama</surname><given-names>Shigeo</given-names></name><xref rid="AF6">6</xref></contrib><contrib contrib-type="author"><name><surname>Yamamoto</surname><given-names>Mitsutoshi</given-names></name><xref rid="AF7">7</xref></contrib><contrib contrib-type="author"><name><surname>Hattori</surname><given-names>Nobutaka</given-names></name><xref rid="AF4">4</xref></contrib><contrib contrib-type="author"><name><surname>Murata</surname><given-names>Miho</given-names></name><xref rid="AF8">8</xref></contrib><contrib contrib-type="author"><name><surname>Toda</surname><given-names>Tatsushi</given-names></name><xref rid="AF1">1</xref><xref rid="AF2">2</xref><xref rid="COR1">*</xref></contrib><aff id="AF1"><sup>1</sup>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</aff><aff id="AF2"><sup>2</sup>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</aff><aff id="AF3"><sup>3</sup>Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 259-1193, Japan,</aff><aff id="AF4"><sup>4</sup>Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan,</aff><aff id="AF5"><sup>5</sup>Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan,</aff><aff id="AF6"><sup>6</sup>Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan,</aff><aff id="AF7"><sup>7</sup>Department of Neurology, Kagawa Prefectural Central Hospital, Takamatsu 760-8557, Japan and</aff><aff id="AF8"><sup>8</sup>Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan</aff></contrib-group><author-notes><corresp id="COR1"><label>*</label>To whom correspondence should be addressed. Tel: +81 668793380; Fax: +81 668793389; Email: <ext-link xlink:href="toda@clgene.med.osaka-u.ac.jp" ext-link-type="email">toda@clgene.med.osaka-u.ac.jp</ext-link></corresp></author-notes><pub-date pub-type="epub"><day>24</day><month>02</month><year>2006</year></pub-date><pub-date pub-type="ppub"><day>1</day><month>April</month><year>2006</year></pub-date><volume>15</volume><issue>7</issue><fpage>1151</fpage><lpage>1158</lpage><history><date date-type="accepted"><day>15</day><month>02</month><year>2006</year></date><date date-type="received"><day>22</day><month>12</month><year>2005</year></date></history><permissions><copyright-statement>© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2006</copyright-year></permissions><self-uri content-type="arthw-pdf" xlink:href="ddl030"></self-uri><abstract xml:lang="en"><p>Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. PD is a complex disorder with multiple genetic and environmental factors influencing disease risk. To identify susceptible genes for sporadic PD, we performed case–control association studies of 268 single nucleotide polymorphisms (SNPs) in 121 candidate genes. In two independent case–control populations, we found that a SNP in <italic>α-synuclein</italic> (<italic>SNCA</italic>), rs7684318, showed the strongest association with PD (<italic>P</italic>=5.0×10<sup>−10</sup>). Linkage disequilibrium (LD) analysis using 29 SNPs in a region around rs7684318 revealed that the entire <italic>SNCA</italic> gene lies within a single LD block (<italic>D</italic>′>0.9) spanning ∼120 kb. A tight LD group (<italic>r</italic><sup>2</sup>>0.85) of six SNPs, including rs7684318, associated most strongly with PD (<italic>P</italic>=2.0×10<sup>−9</sup>–1.7×10<sup>−11</sup>). Haplotype association analysis did not show lower <italic>P</italic>-values than any single SNP within this group. SNCA is a major component of Lewy bodies, the pathological hallmark of PD. Aggregation of SNCA is thought to play a crucial role in PD. <italic>SNCA</italic> expression levels tended to be positively correlated with the number of the associated allele in autopsied frontal cortices. These findings establish <italic>SNCA</italic> as a definite susceptibility gene for sporadic PD.</p></abstract><custom-meta-wrap><custom-meta><meta-name>hwp-legacy-fpage</meta-name><meta-value>1151</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>1 April 2006</meta-value></custom-meta><custom-meta><meta-name>hwp-legacy-dochead</meta-name><meta-value>Article</meta-value></custom-meta></custom-meta-wrap></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Multiple candidate gene analysis identifies α-synuclein as a susceptibility gene for sporadic Parkinson's disease</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Multiple candidate gene analysis identifies α-synuclein as a susceptibility gene for sporadic Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Ikuko</namePart><namePart type="family">Mizuta</namePart><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Wataru</namePart><namePart type="family">Satake</namePart><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yuko</namePart><namePart type="family">Nakabayashi</namePart><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation><affiliation>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Chiyomi</namePart><namePart type="family">Ito</namePart><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation><affiliation>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Satoko</namePart><namePart type="family">Suzuki</namePart><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation><affiliation>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yoshio</namePart><namePart type="family">Momose</namePart><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yoshitaka</namePart><namePart type="family">Nagai</namePart><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Akira</namePart><namePart type="family">Oka</namePart><affiliation>Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 259-1193, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hidetoshi</namePart><namePart type="family">Inoko</namePart><affiliation>Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 259-1193, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jiro</namePart><namePart type="family">Fukae</namePart><affiliation>Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yuko</namePart><namePart type="family">Saito</namePart><affiliation>Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan,</affiliation><affiliation>Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Motoji</namePart><namePart type="family">Sawabe</namePart><affiliation>Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Shigeo</namePart><namePart type="family">Murayama</namePart><affiliation>Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mitsutoshi</namePart><namePart type="family">Yamamoto</namePart><affiliation>Department of Neurology, Kagawa Prefectural Central Hospital, Takamatsu 760-8557, Japan and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nobutaka</namePart><namePart type="family">Hattori</namePart><affiliation>Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Miho</namePart><namePart type="family">Murata</namePart><affiliation>Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Tatsushi</namePart><namePart type="family">Toda</namePart><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan,</affiliation><affiliation>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan,</affiliation><affiliation>E-mail: toda@clgene.med.osaka-u.ac.jp</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2006-04-01</dateIssued><dateCreated encoding="w3cdtf">2006-02-24</dateCreated><copyrightDate encoding="w3cdtf">2006</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. PD is a complex disorder with multiple genetic and environmental factors influencing disease risk. To identify susceptible genes for sporadic PD, we performed case–control association studies of 268 single nucleotide polymorphisms (SNPs) in 121 candidate genes. In two independent case–control populations, we found that a SNP in α-synuclein (SNCA), rs7684318, showed the strongest association with PD (P=5.0×10−10). Linkage disequilibrium (LD) analysis using 29 SNPs in a region around rs7684318 revealed that the entire SNCA gene lies within a single LD block (D′>0.9) spanning ∼120 kb. A tight LD group (r2>0.85) of six SNPs, including rs7684318, associated most strongly with PD (P=2.0×10−9–1.7×10−11). Haplotype association analysis did not show lower P-values than any single SNP within this group. SNCA is a major component of Lewy bodies, the pathological hallmark of PD. Aggregation of SNCA is thought to play a crucial role in PD. SNCA expression levels tended to be positively correlated with the number of the associated allele in autopsied frontal cortices. These findings establish SNCA as a definite susceptibility gene for sporadic PD.</abstract><note type="author-notes">*To whom correspondence should be addressed. Tel: +81 668793380; Fax: +81 668793389; Email: toda@clgene.med.osaka-u.ac.jp</note><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><titleInfo type="abbreviated"><title>Hum. Mol. Genet.</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0964-6906</identifier><identifier type="eISSN">1460-2083</identifier><identifier type="PublisherID">hmg</identifier><identifier type="PublisherID-hwp">hmg</identifier><identifier type="PublisherID-nlm-ta">Hum Mol Genet</identifier><part><date>2006</date><detail type="volume"><caption>vol.</caption><number>15</number></detail><detail type="issue"><caption>no.</caption><number>7</number></detail><extent unit="pages"><start>1151</start><end>1158</end></extent></part></relatedItem><identifier type="istex">D66103F44B7C0A027672E53C0AC8CA54EFD09265</identifier><identifier type="DOI">10.1093/hmg/ddl030</identifier><identifier type="href">ddl030</identifier><identifier type="local">ddl030</identifier><accessCondition type="use and reproduction" contentType="copyright">© The Author 2006. Published by Oxford University Press. All rights reserved. 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