Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette disorder
Identifieur interne : 000323 ( Pmc/Curation ); précédent : 000322; suivant : 000324Common 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.
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
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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></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></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><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">8610688</journal-id><journal-id journal-id-type="pubmed-jr-id">5937</journal-id><journal-id journal-id-type="nlm-ta">Mov Disord</journal-id><journal-id journal-id-type="iso-abbrev">Mov. Disord.</journal-id><journal-title-group><journal-title>Movement disorders : official journal of the Movement Disorder Society</journal-title></journal-title-group><issn pub-type="ppub">0885-3185</issn><issn pub-type="epub">1531-8257</issn></journal-meta><article-meta><article-id pub-id-type="pmid">23630162</article-id><article-id pub-id-type="pmc">3766488</article-id><article-id pub-id-type="doi">10.1002/mds.25460</article-id><article-id pub-id-type="manuscript">NIHMS461150</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Common and rare alleles of the serotonin transporter gene, <italic>SLC6A4</italic>, associated with Tourette disorder</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Moya</surname><given-names>Pablo R</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wendland</surname><given-names>Jens R</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FN1">#</xref></contrib><contrib contrib-type="author"><name><surname>Rubenstein</surname><given-names>Liza M</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Timpano</surname><given-names>Kiara R</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Heiman</surname><given-names>Gary A</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Tischfield</surname><given-names>Jay A</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>King</surname><given-names>Robert A</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Andrews</surname><given-names>Anne M</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Ramamoorthy</surname><given-names>Samanda</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>McMahon</surname><given-names>Francis J</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Murphy</surname><given-names>Dennis L</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib></contrib-group><aff id="A1"><label>1</label>Laboratory of Clinical Science, NIMH-Intramural Research Program, Bethesda, MD</aff><aff id="A2"><label>2</label>Department of Psychology, University of Miami, Coral Gables, FL</aff><aff id="A3"><label>3</label>Human Genetics Institute of New Jersey and Department of Genetics, Rutgers University, Piscataway, NJ</aff><aff id="A4"><label>4</label>Child Study Center of Yale University, New Haven, CT</aff><aff id="A5"><label>5</label>Semel Institute for Neuroscience and Human Behavior and California Nano Systems Institute, University of California, Los Angeles, CA</aff><aff id="A6"><label>6</label>Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA</aff><aff id="A7"><label>7</label>Human Genetics Branch, NIMH-Intramural Research Program, Bethesda, MD</aff><author-notes><fn id="FN1" fn-type="present-address"><label>#</label><p id="P1">Present address: Worldwide R&D, Pfizer Inc, Cambridge, MA, USA</p></fn><fn id="FN2"><p id="P2">P.R. Moya: Conceived, organized and executed the research project; executed statistical analysis; wrote first manuscript draft.</p><p id="P3">D.L. Murphy: Conceived research project; executed and reviewed statistical analysis; reviewed and critiqued manuscript.</p><p id="P4">J.R. Wendland: Conceived research project; designed, executed and reviewed statistical analysis; reviewed and critiqued manuscript.</p><p id="P5">L.M. Rubenstein: Performed experimental work and statistical analysis; reviewed and critiqued manuscript.</p><p id="P6">K.C. Timpano: Conceived research project; recruited FL healthy volunteers Reviewed and critiqued statistical analysis; reviewed and critiqued manuscript.</p><p id="P7">G.A. Heiman, J.A. Tischfield and R.A. King: Recruited and clinically characterized Tourette probands; reviewed statistical analysis; reviewed and critiqued manuscript.</p><p id="P8">S. Ramamoorthy, A.M. Andrews and F.J. McMahon: Reviewed and critiqued statistical analysis; reviewed and critiqued manuscript.</p></fn><corresp id="CR1"><underline>Corresponding author</underline> Pablo R. Moya, PhD Laboratory of Clinical Science, NIMH-IRP 10/3D41 10 Center Dr Bethesda, MD 20892 Phone 301-5940126; Fax 301-4020188 <email>moyap@mail.nih.gov</email></corresp></author-notes><pub-date pub-type="nihms-submitted"><day>17</day><month>4</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>29</day><month>4</month><year>2013</year></pub-date><pub-date pub-type="ppub"><month>8</month><year>2013</year></pub-date><pub-date pub-type="pmc-release"><day>01</day><month>8</month><year>2014</year></pub-date><volume>28</volume><issue>9</issue><fpage>1263</fpage><lpage>1270</lpage><abstract><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></abstract><kwd-group><kwd><italic>SLC6A4</italic></kwd><kwd>SERT</kwd><kwd>Tourette</kwd><kwd>serotonin</kwd><kwd>5-HTTLPR</kwd><kwd>SERT I425V</kwd></kwd-group><funding-group><award-group><funding-source country="United States">National Institute of Mental Health : NIMH</funding-source><award-id>R01 MH092293 || MH</award-id></award-group><award-group><funding-source country="United States">National Institute of Mental Health : NIMH</funding-source><award-id>R01 MH064756 || MH</award-id></award-group><award-group><funding-source country="United States">National Institute of Mental Health : NIMH</funding-source><award-id>ZIA MH000336-30 || MH</award-id></award-group><award-group><funding-source country="United States">National Institute of Mental Health : NIMH</funding-source><award-id>Z99 MH999999 || MH</award-id></award-group><award-group><funding-source country="United States">National Institute of Mental Health : NIMH</funding-source><award-id>Z99 MH999999 || MH</award-id></award-group><award-group><funding-source country="United States">National Institute of Mental Health : NIMH</funding-source><award-id>Z99 MH999999 || MH</award-id></award-group><award-group><funding-source country="United States">National Institute of Mental Health : NIMH</funding-source><award-id>Z01 MH000336-28 || MH</award-id></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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