Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette disorder
Identifieur interne : 000A47 ( Main/Exploration ); précédent : 000A46; suivant : 000A48Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette disorder
Auteurs : Pablo R. Moya [États-Unis] ; Jens R. Wendland [États-Unis] ; Liza M. Rubenstein [États-Unis] ; Kiara R. Timpano [États-Unis] ; Gary A. Heiman [États-Unis] ; Jay A. Tischfield [États-Unis] ; Robert A. King [États-Unis] ; Anne M. Andrews [États-Unis] ; Samanda Ramamoorthy [États-Unis] ; Francis J. Mcmahon [États-Unis] ; Dennis L. Murphy [États-Unis]Source :
- Movement disorders : official journal of the Movement Disorder Society [ 0885-3185 ] ; 2013.
English descriptors
- KwdEn :
- Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease (genetics), Genotype, Humans, Male, Obsessive-Compulsive Disorder (genetics), Polymorphism, Single Nucleotide (genetics), Psychiatric Status Rating Scales, Serotonin Plasma Membrane Transport Proteins (genetics), Tourette Syndrome (genetics).
- MESH :
- chemical , genetics : Serotonin Plasma Membrane Transport Proteins.
- genetics : Genetic Predisposition to Disease, Obsessive-Compulsive Disorder, Polymorphism, Single Nucleotide, Tourette Syndrome.
- Female, Gene Frequency, Genetic Association Studies, Genotype, Humans, Male, Psychiatric Status Rating Scales.
Abstract
To evaluate the hypothesis that functionally over-expressing alleles of the serotonin transporter gene
We genotyped the refined 5-HTTLPR/rs25531 locus and the associated rs25532 variant in the
The higher-expressing 5-HTTLPR/rs25531 LA allele was more prevalent in TD probands than controls (χ2=5.75, p=0.017, OR=1.35), and in a secondary analysis, surprisingly found to be significantly more frequent in probands with TD alone than in those with TD plus OCD (Fisher's exact test, p=0.0006, OR=2.29). Likewise, the higher-expressing LAC haplotype (5-HTTLPR/rs25531/rs25532) was more frequent in TD probands than controls (p=0.024, OR=1.33) and likewise in the TD alone versus TD plus OCD group (p=0.0013, OR=2.14). Further, the rare gain-of-function SERT I425V variant was found in three male siblings with TD and/or OCD and in their father. The cumulative count of SERT I425V thus becomes 1.57% in OCD/TD spectrum conditions vs. 0.15% in controls, with a recalculated, family-adjusted significance of χ2=15.03, p < 0.0001, OR=9.0 (total worldwide genotyped=2914).
This report provides a unique combination of common and rare variants in one gene in TD, all found to be associated with
Url:
DOI: 10.1002/mds.25460
PubMed: 23630162
PubMed Central: 3766488
Affiliations:
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Heiman</name><affiliation wicri:level="2"><nlm:aff id="A3">Human Genetics Institute of New Jersey and Department of Genetics, Rutgers University, Piscataway, NJ</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">New Jersey</region></placeName><wicri:cityArea>Human Genetics Institute of New Jersey and Department of Genetics, Rutgers University, Piscataway</wicri:cityArea></affiliation></author><author><name sortKey="Tischfield, Jay A" sort="Tischfield, Jay A" uniqKey="Tischfield J" first="Jay A" last="Tischfield">Jay A. 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Mcmahon</name><affiliation wicri:level="2"><nlm:aff id="A7">Human Genetics Branch, NIMH-Intramural Research Program, Bethesda, MD</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Human Genetics Branch, NIMH-Intramural Research Program, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Murphy, Dennis L" sort="Murphy, Dennis L" uniqKey="Murphy D" first="Dennis L" last="Murphy">Dennis L. Murphy</name><affiliation wicri:level="2"><nlm:aff id="A1">Laboratory of Clinical Science, NIMH-Intramural Research Program, Bethesda, MD</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Laboratory of Clinical Science, NIMH-Intramural Research Program, Bethesda</wicri:cityArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23630162</idno><idno type="pmc">3766488</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766488</idno><idno type="RBID">PMC:3766488</idno><idno type="doi">10.1002/mds.25460</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">000323</idno><idno type="wicri:Area/Pmc/Curation">000323</idno><idno type="wicri:Area/Pmc/Checkpoint">000132</idno><idno type="wicri:source">PubMed</idno><idno type="wicri:Area/PubMed/Corpus">000929</idno><idno type="wicri:Area/PubMed/Curation">000929</idno><idno type="wicri:Area/PubMed/Checkpoint">000A57</idno><idno type="wicri:Area/Ncbi/Merge">003B52</idno><idno type="wicri:Area/Ncbi/Curation">003B52</idno><idno type="wicri:Area/Ncbi/Checkpoint">003B52</idno><idno type="wicri:doubleKey">0885-3185:2013:Moya P:common:and:rare</idno><idno type="wicri:Area/Main/Merge">000A47</idno><idno type="wicri:Area/Main/Curation">000A47</idno><idno type="wicri:Area/Main/Exploration">000A47</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Common and rare alleles of the serotonin transporter gene, <italic>SLC6A4</italic>, associated with Tourette disorder</title><author><name sortKey="Moya, Pablo R" sort="Moya, Pablo R" uniqKey="Moya P" first="Pablo R" last="Moya">Pablo R. Moya</name><affiliation wicri:level="2"><nlm:aff id="A1">Laboratory of Clinical Science, NIMH-Intramural Research Program, Bethesda, MD</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Laboratory of Clinical Science, NIMH-Intramural Research Program, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Wendland, Jens R" sort="Wendland, Jens R" uniqKey="Wendland J" first="Jens R" last="Wendland">Jens R. Wendland</name><affiliation wicri:level="2"><nlm:aff id="A1">Laboratory of Clinical Science, NIMH-Intramural Research Program, Bethesda, MD</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Laboratory of Clinical Science, NIMH-Intramural Research Program, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Rubenstein, Liza M" sort="Rubenstein, Liza M" uniqKey="Rubenstein L" first="Liza M" last="Rubenstein">Liza M. Rubenstein</name><affiliation wicri:level="2"><nlm:aff id="A1">Laboratory of Clinical Science, NIMH-Intramural Research Program, Bethesda, MD</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Laboratory of Clinical Science, NIMH-Intramural Research Program, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Timpano, Kiara R" sort="Timpano, Kiara R" uniqKey="Timpano K" first="Kiara R" last="Timpano">Kiara R. Timpano</name><affiliation wicri:level="2"><nlm:aff id="A2">Department of Psychology, University of Miami, Coral Gables, FL</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Floride</region></placeName><wicri:cityArea>Department of Psychology, University of Miami, Coral Gables</wicri:cityArea></affiliation></author><author><name sortKey="Heiman, Gary A" sort="Heiman, Gary A" uniqKey="Heiman G" first="Gary A" last="Heiman">Gary A. Heiman</name><affiliation wicri:level="2"><nlm:aff id="A3">Human Genetics Institute of New Jersey and Department of Genetics, Rutgers University, Piscataway, NJ</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">New Jersey</region></placeName><wicri:cityArea>Human Genetics Institute of New Jersey and Department of Genetics, Rutgers University, Piscataway</wicri:cityArea></affiliation></author><author><name sortKey="Tischfield, Jay A" sort="Tischfield, Jay A" uniqKey="Tischfield J" first="Jay A" last="Tischfield">Jay A. Tischfield</name><affiliation wicri:level="2"><nlm:aff id="A3">Human Genetics Institute of New Jersey and Department of Genetics, Rutgers University, Piscataway, NJ</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">New Jersey</region></placeName><wicri:cityArea>Human Genetics Institute of New Jersey and Department of Genetics, Rutgers University, Piscataway</wicri:cityArea></affiliation></author><author><name sortKey="King, Robert A" sort="King, Robert A" uniqKey="King R" first="Robert A" last="King">Robert A. King</name><affiliation wicri:level="2"><nlm:aff id="A4">Child Study Center of Yale University, New Haven, CT</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Connecticut</region></placeName><wicri:cityArea>Child Study Center of Yale University, New Haven</wicri:cityArea></affiliation></author><author><name sortKey="Andrews, Anne M" sort="Andrews, Anne M" uniqKey="Andrews A" first="Anne M" last="Andrews">Anne M. Andrews</name><affiliation wicri:level="2"><nlm:aff id="A5">Semel Institute for Neuroscience and Human Behavior and California Nano Systems Institute, University of California, Los Angeles, CA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Semel Institute for Neuroscience and Human Behavior and California Nano Systems Institute, University of California, Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Ramamoorthy, Samanda" sort="Ramamoorthy, Samanda" uniqKey="Ramamoorthy S" first="Samanda" last="Ramamoorthy">Samanda Ramamoorthy</name><affiliation wicri:level="2"><nlm:aff id="A6">Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Virginie</region></placeName><wicri:cityArea>Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond</wicri:cityArea></affiliation></author><author><name sortKey="Mcmahon, Francis J" sort="Mcmahon, Francis J" uniqKey="Mcmahon F" first="Francis J" last="Mcmahon">Francis J. Mcmahon</name><affiliation wicri:level="2"><nlm:aff id="A7">Human Genetics Branch, NIMH-Intramural Research Program, Bethesda, MD</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Human Genetics Branch, NIMH-Intramural Research Program, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Murphy, Dennis L" sort="Murphy, Dennis L" uniqKey="Murphy D" first="Dennis L" last="Murphy">Dennis L. Murphy</name><affiliation wicri:level="2"><nlm:aff id="A1">Laboratory of Clinical Science, NIMH-Intramural Research Program, Bethesda, MD</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Laboratory of Clinical Science, NIMH-Intramural Research Program, Bethesda</wicri:cityArea></affiliation></author></analytic><series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Female</term><term>Gene Frequency</term><term>Genetic Association Studies</term><term>Genetic Predisposition to Disease (genetics)</term><term>Genotype</term><term>Humans</term><term>Male</term><term>Obsessive-Compulsive Disorder (genetics)</term><term>Polymorphism, Single Nucleotide (genetics)</term><term>Psychiatric Status Rating Scales</term><term>Serotonin Plasma Membrane Transport Proteins (genetics)</term><term>Tourette Syndrome (genetics)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Serotonin Plasma Membrane Transport Proteins</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Genetic Predisposition to Disease</term><term>Obsessive-Compulsive Disorder</term><term>Polymorphism, Single Nucleotide</term><term>Tourette Syndrome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Female</term><term>Gene Frequency</term><term>Genetic Association Studies</term><term>Genotype</term><term>Humans</term><term>Male</term><term>Psychiatric Status Rating Scales</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>BACKGROUND</title><p id="P9">To evaluate the hypothesis that functionally over-expressing alleles of the serotonin transporter gene <italic>SLC6A4</italic> are present in Tourette disorder (TD), just as we have found in obsessive compulsive disorder (OCD), we evaluated TD probands (N=151) and controls (N=858).</p></sec><sec id="S2"><title>METHODS</title><p id="P10">We genotyped the refined 5-HTTLPR/rs25531 locus and the associated rs25532 variant in the <italic>SLC6A4</italic> promoter plus the rare coding variant SERT I425V.</p></sec><sec id="S3"><title>RESULTS</title><p id="P11">The higher-expressing 5-HTTLPR/rs25531 L<sub>A</sub> allele was more prevalent in TD probands than controls (χ<sup>2</sup>=5.75, p=0.017, OR=1.35), and in a secondary analysis, surprisingly found to be significantly more frequent in probands with TD alone than in those with TD plus OCD (Fisher's exact test, p=0.0006, OR=2.29). Likewise, the higher-expressing L<sub>AC</sub> haplotype (5-HTTLPR/rs25531/rs25532) was more frequent in TD probands than controls (p=0.024, OR=1.33) and likewise in the TD alone versus TD plus OCD group (p=0.0013, OR=2.14). Further, the rare gain-of-function SERT I425V variant was found in three male siblings with TD and/or OCD and in their father. The cumulative count of SERT I425V thus becomes 1.57% in OCD/TD spectrum conditions vs. 0.15% in controls, with a recalculated, family-adjusted significance of χ<sup>2</sup>=15.03, p < 0.0001, OR=9.0 (total worldwide genotyped=2914).</p></sec><sec id="S4"><title>CONCLUSIONS</title><p id="P12">This report provides a unique combination of common and rare variants in one gene in TD, all found to be associated with <italic>SLC6A4</italic> gain of function. Thus, altered SERT activity represents a potential contributor to serotonergic abnormalities in TD. Present results call for replication in a similarly intensively evaluated sample.</p></sec></div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Californie</li><li>Connecticut</li><li>Floride</li><li>Maryland</li><li>New Jersey</li><li>Virginie</li></region></list><tree><country name="États-Unis"><region name="Maryland"><name sortKey="Moya, Pablo R" sort="Moya, Pablo R" uniqKey="Moya P" first="Pablo R" last="Moya">Pablo R. Moya</name></region><name sortKey="Andrews, Anne M" sort="Andrews, Anne M" uniqKey="Andrews A" first="Anne M" last="Andrews">Anne M. Andrews</name><name sortKey="Heiman, Gary A" sort="Heiman, Gary A" uniqKey="Heiman G" first="Gary A" last="Heiman">Gary A. Heiman</name><name sortKey="King, Robert A" sort="King, Robert A" uniqKey="King R" first="Robert A" last="King">Robert A. King</name><name sortKey="Mcmahon, Francis J" sort="Mcmahon, Francis J" uniqKey="Mcmahon F" first="Francis J" last="Mcmahon">Francis J. Mcmahon</name><name sortKey="Murphy, Dennis L" sort="Murphy, Dennis L" uniqKey="Murphy D" first="Dennis L" last="Murphy">Dennis L. Murphy</name><name sortKey="Ramamoorthy, Samanda" sort="Ramamoorthy, Samanda" uniqKey="Ramamoorthy S" first="Samanda" last="Ramamoorthy">Samanda Ramamoorthy</name><name sortKey="Rubenstein, Liza M" sort="Rubenstein, Liza M" uniqKey="Rubenstein L" first="Liza M" last="Rubenstein">Liza M. Rubenstein</name><name sortKey="Timpano, Kiara R" sort="Timpano, Kiara R" uniqKey="Timpano K" first="Kiara R" last="Timpano">Kiara R. Timpano</name><name sortKey="Tischfield, Jay A" sort="Tischfield, Jay A" uniqKey="Tischfield J" first="Jay A" last="Tischfield">Jay A. Tischfield</name><name sortKey="Wendland, Jens R" sort="Wendland, Jens R" uniqKey="Wendland J" first="Jens R" last="Wendland">Jens R. Wendland</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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