Increased Nigral SLC6A3 Activity in Schizophrenia Patients: Findings From the Toronto–McLean Cohorts
Identifieur interne : 000130 ( Pmc/Curation ); précédent : 000129; suivant : 000131Increased Nigral SLC6A3 Activity in Schizophrenia Patients: Findings From the Toronto–McLean Cohorts
Auteurs : James L. Kennedy [Canada] ; Nian Xiong [République populaire de Chine] ; Jinlong Yu ; Clement C. Zai [Canada] ; Jennie G. Pouget [Canada] ; Jie Li [République populaire de Chine] ; Kefu Liu [République populaire de Chine] ; Hong Qing [République populaire de Chine] ; Tao Wang [République populaire de Chine] ; Eden Martin ; Deborah L. Levy [États-Unis] ; Zhicheng LinSource :
- Schizophrenia Bulletin [ 0586-7614 ] ; 2015.
Abstract
Url:
DOI: 10.1093/schbul/sbv191
PubMed: 26707863
PubMed Central: 4838105
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Activity in Schizophrenia Patients: Findings From the Toronto–McLean Cohorts</title>
<author><name sortKey="Kennedy, James L" sort="Kennedy, James L" uniqKey="Kennedy J" first="James L." last="Kennedy">James L. Kennedy</name>
<affiliation wicri:level="1"><nlm:aff id="AF0001"><institution>Neurogenetics Section, Neuroscience Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health</institution>
,<addr-line>Toronto, Ontario</addr-line>
,<country>Canada</country>
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<country xml:lang="fr">Canada</country>
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<affiliation wicri:level="1"><nlm:aff id="AF0002"><institution>Department of Psychiatry, University of Toronto</institution>
,<addr-line>Toronto, Ontario</addr-line>
,<country>Canada</country>
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<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="AF0003"><institution>Institute of Medical Science, University of Toronto</institution>
,<addr-line>Toronto, Ontario</addr-line>
,<country>Canada</country>
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<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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</author>
<author><name sortKey="Xiong, Nian" sort="Xiong, Nian" uniqKey="Xiong N" first="Nian" last="Xiong">Nian Xiong</name>
<affiliation><nlm:aff id="AF0004"><institution>Laboratory of Psychiatric Neurogenomics, McLean Hospital</institution>
,<addr-line>Belmont, MA</addr-line>
;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="AF0005"><institution>Department of Psychiatry, Harvard Medical School</institution>
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<affiliation wicri:level="1"><nlm:aff id="AF0006"><institution>Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology</institution>
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<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Yu, Jinlong" sort="Yu, Jinlong" uniqKey="Yu J" first="Jinlong" last="Yu">Jinlong Yu</name>
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,<addr-line>Belmont, MA</addr-line>
;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="AF0005"><institution>Department of Psychiatry, Harvard Medical School</institution>
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<author><name sortKey="Zai, Clement C" sort="Zai, Clement C" uniqKey="Zai C" first="Clement C." last="Zai">Clement C. Zai</name>
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<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="AF0002"><institution>Department of Psychiatry, University of Toronto</institution>
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<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Pouget, Jennie G" sort="Pouget, Jennie G" uniqKey="Pouget J" first="Jennie G." last="Pouget">Jennie G. Pouget</name>
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,<addr-line>Toronto, Ontario</addr-line>
,<country>Canada</country>
;</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="AF0002"><institution>Department of Psychiatry, University of Toronto</institution>
,<addr-line>Toronto, Ontario</addr-line>
,<country>Canada</country>
;</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="AF0003"><institution>Institute of Medical Science, University of Toronto</institution>
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<country xml:lang="fr">Canada</country>
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<author><name sortKey="Li, Jie" sort="Li, Jie" uniqKey="Li J" first="Jie" last="Li">Jie Li</name>
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,<addr-line>Belmont, MA</addr-line>
;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="AF0005"><institution>Department of Psychiatry, Harvard Medical School</institution>
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;</nlm:aff>
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,<addr-line>Tianjin</addr-line>
,<country>China</country>
;</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Liu, Kefu" sort="Liu, Kefu" uniqKey="Liu K" first="Kefu" last="Liu">Kefu Liu</name>
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,<addr-line>Belmont, MA</addr-line>
;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="AF0005"><institution>Department of Psychiatry, Harvard Medical School</institution>
,<addr-line>Boston, MA</addr-line>
;</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="AF0008"><institution>School of Life Science, Beijing Institute of Technology</institution>
,<addr-line>Beijing</addr-line>
,<country>China</country>
;</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Qing, Hong" sort="Qing, Hong" uniqKey="Qing H" first="Hong" last="Qing">Hong Qing</name>
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;</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Wang, Tao" sort="Wang, Tao" uniqKey="Wang T" first="Tao" last="Wang">Tao Wang</name>
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,<addr-line>Wuhan</addr-line>
,<country>China</country>
;</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Martin, Eden" sort="Martin, Eden" uniqKey="Martin E" first="Eden" last="Martin">Eden Martin</name>
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;</nlm:aff>
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Belmont</wicri:cityArea>
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<author><name sortKey="Lin, Zhicheng" sort="Lin, Zhicheng" uniqKey="Lin Z" first="Zhicheng" last="Lin">Zhicheng Lin</name>
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,<addr-line>Belmont, MA</addr-line>
;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="AF0005"><institution>Department of Psychiatry, Harvard Medical School</institution>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Increased Nigral <italic>SLC6A3</italic>
Activity in Schizophrenia Patients: Findings From the Toronto–McLean Cohorts</title>
<author><name sortKey="Kennedy, James L" sort="Kennedy, James L" uniqKey="Kennedy J" first="James L." last="Kennedy">James L. Kennedy</name>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Xiong, Nian" sort="Xiong, Nian" uniqKey="Xiong N" first="Nian" last="Xiong">Nian Xiong</name>
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;</nlm:aff>
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,<addr-line>Wuhan</addr-line>
,<country>China</country>
;</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
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<author><name sortKey="Yu, Jinlong" sort="Yu, Jinlong" uniqKey="Yu J" first="Jinlong" last="Yu">Jinlong Yu</name>
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<author><name sortKey="Zai, Clement C" sort="Zai, Clement C" uniqKey="Zai C" first="Clement C." last="Zai">Clement C. Zai</name>
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,<addr-line>Toronto, Ontario</addr-line>
,<country>Canada</country>
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<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="AF0002"><institution>Department of Psychiatry, University of Toronto</institution>
,<addr-line>Toronto, Ontario</addr-line>
,<country>Canada</country>
;</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="AF0003"><institution>Institute of Medical Science, University of Toronto</institution>
,<addr-line>Toronto, Ontario</addr-line>
,<country>Canada</country>
;</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pouget, Jennie G" sort="Pouget, Jennie G" uniqKey="Pouget J" first="Jennie G." last="Pouget">Jennie G. Pouget</name>
<affiliation wicri:level="1"><nlm:aff id="AF0001"><institution>Neurogenetics Section, Neuroscience Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health</institution>
,<addr-line>Toronto, Ontario</addr-line>
,<country>Canada</country>
;</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="AF0002"><institution>Department of Psychiatry, University of Toronto</institution>
,<addr-line>Toronto, Ontario</addr-line>
,<country>Canada</country>
;</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="AF0003"><institution>Institute of Medical Science, University of Toronto</institution>
,<addr-line>Toronto, Ontario</addr-line>
,<country>Canada</country>
;</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Li, Jie" sort="Li, Jie" uniqKey="Li J" first="Jie" last="Li">Jie Li</name>
<affiliation><nlm:aff id="AF0004"><institution>Laboratory of Psychiatric Neurogenomics, McLean Hospital</institution>
,<addr-line>Belmont, MA</addr-line>
;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="AF0005"><institution>Department of Psychiatry, Harvard Medical School</institution>
,<addr-line>Boston, MA</addr-line>
;</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="AF0007"><institution>Institute of Psychiatry, Tianjin Mental Health Center</institution>
,<addr-line>Tianjin</addr-line>
,<country>China</country>
;</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Liu, Kefu" sort="Liu, Kefu" uniqKey="Liu K" first="Kefu" last="Liu">Kefu Liu</name>
<affiliation><nlm:aff id="AF0004"><institution>Laboratory of Psychiatric Neurogenomics, McLean Hospital</institution>
,<addr-line>Belmont, MA</addr-line>
;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="AF0005"><institution>Department of Psychiatry, Harvard Medical School</institution>
,<addr-line>Boston, MA</addr-line>
;</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="AF0008"><institution>School of Life Science, Beijing Institute of Technology</institution>
,<addr-line>Beijing</addr-line>
,<country>China</country>
;</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Qing, Hong" sort="Qing, Hong" uniqKey="Qing H" first="Hong" last="Qing">Hong Qing</name>
<affiliation wicri:level="1"><nlm:aff id="AF0008"><institution>School of Life Science, Beijing Institute of Technology</institution>
,<addr-line>Beijing</addr-line>
,<country>China</country>
;</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Wang, Tao" sort="Wang, Tao" uniqKey="Wang T" first="Tao" last="Wang">Tao Wang</name>
<affiliation wicri:level="1"><nlm:aff id="AF0006"><institution>Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology</institution>
,<addr-line>Wuhan</addr-line>
,<country>China</country>
;</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Martin, Eden" sort="Martin, Eden" uniqKey="Martin E" first="Eden" last="Martin">Eden Martin</name>
<affiliation><nlm:aff id="AF0009"><institution>Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami</institution>
,<addr-line>Miami, FL</addr-line>
;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Levy, Deborah L" sort="Levy, Deborah L" uniqKey="Levy D" first="Deborah L." last="Levy">Deborah L. Levy</name>
<affiliation><nlm:aff id="AF0005"><institution>Department of Psychiatry, Harvard Medical School</institution>
,<addr-line>Boston, MA</addr-line>
;</nlm:aff>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="AF0010"><institution>Psychology Research Laboratory, McLean Hospital</institution>
,<addr-line>Belmont, MA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Belmont</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Lin, Zhicheng" sort="Lin, Zhicheng" uniqKey="Lin Z" first="Zhicheng" last="Lin">Zhicheng Lin</name>
<affiliation><nlm:aff id="AF0004"><institution>Laboratory of Psychiatric Neurogenomics, McLean Hospital</institution>
,<addr-line>Belmont, MA</addr-line>
;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="AF0005"><institution>Department of Psychiatry, Harvard Medical School</institution>
,<addr-line>Boston, MA</addr-line>
;</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Schizophrenia Bulletin</title>
<idno type="ISSN">0586-7614</idno>
<idno type="eISSN">1745-1701</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
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<front><div type="abstract" xml:lang="en"><p><italic>SLC6A3</italic>
, which encodes the primary regulator of extracellular dopamine (DA) concentration, the DA transporter, has been implicated in schizophrenia (SCZ). However, the details of its genetic effect on risk remain largely unknown. The purpose of this candidate gene study was to identify a specific <italic>SLC6A3</italic>
activity associated with SCZ by using functional genetic approaches. We first examined gene activity in DA neurons isolated from case-control postmortem nigral tissue and found that the average <italic>SLC6A3</italic>
mRNA level in controls was only 0.37-fold of that in cases (<italic>P</italic>
= .0034). To understand this expression difference, we examined the association of 10 genetic markers, mostly located in the promoter region, with SCZ in 1717 subjects collected from Toronto and McLean cohorts, including 881 controls and 836 cases and identified the 5′ promoter SNP rs1478435 as having a significant association signal (uncorrected <italic>P</italic>
value: .00462; adjusted <italic>P</italic>
value: .0319) in unrelated Caucasians. Allele T was over-represented in controls (OR = .75); T-carrier controls had decreased mRNA levels in nigral DA neurons, contributing to the reduced activity in the controls. In vitro functional analysis confirmed that T carriers displayed attenuated enhancement of promoter activity. These findings collectively suggest that increased nigral <italic>SLC6A3</italic>
activity may be a risk factor for SCZ, and may help to explain high rates of comorbidity with substance abuse.</p>
</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>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Schizophr Bull</journal-id>
<journal-id journal-id-type="iso-abbrev">Schizophr Bull</journal-id>
<journal-id journal-id-type="hwp">schbul</journal-id>
<journal-id journal-id-type="publisher-id">schbul</journal-id>
<journal-title-group><journal-title>Schizophrenia Bulletin</journal-title>
</journal-title-group>
<issn pub-type="ppub">0586-7614</issn>
<issn pub-type="epub">1745-1701</issn>
<publisher><publisher-name>Oxford University Press</publisher-name>
<publisher-loc>US</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26707863</article-id>
<article-id pub-id-type="pmc">4838105</article-id>
<article-id pub-id-type="doi">10.1093/schbul/sbv191</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Regular Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Increased Nigral <italic>SLC6A3</italic>
Activity in Schizophrenia Patients: Findings From the Toronto–McLean Cohorts</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Kennedy</surname>
<given-names>James L.</given-names>
</name>
<xref ref-type="aff" rid="AF0001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="AF0002"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="AF0003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Xiong</surname>
<given-names>Nian</given-names>
</name>
<xref ref-type="aff" rid="AF0004"><sup>4</sup>
</xref>
<xref ref-type="aff" rid="AF0005"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="AF0006"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yu</surname>
<given-names>Jinlong</given-names>
</name>
<xref ref-type="aff" rid="AF0004"><sup>4</sup>
</xref>
<xref ref-type="aff" rid="AF0005"><sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zai</surname>
<given-names>Clement C.</given-names>
</name>
<xref ref-type="aff" rid="AF0001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="AF0002"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="AF0003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pouget</surname>
<given-names>Jennie G.</given-names>
</name>
<xref ref-type="aff" rid="AF0001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="AF0002"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="AF0003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Li</surname>
<given-names>Jie</given-names>
</name>
<xref ref-type="aff" rid="AF0004"><sup>4</sup>
</xref>
<xref ref-type="aff" rid="AF0005"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="AF0007"><sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Kefu</given-names>
</name>
<xref ref-type="aff" rid="AF0004"><sup>4</sup>
</xref>
<xref ref-type="aff" rid="AF0005"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="AF0008"><sup>8</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Qing</surname>
<given-names>Hong</given-names>
</name>
<xref ref-type="aff" rid="AF0008"><sup>8</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wang</surname>
<given-names>Tao</given-names>
</name>
<xref ref-type="aff" rid="AF0006"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Martin</surname>
<given-names>Eden</given-names>
</name>
<xref ref-type="aff" rid="AF0009"><sup>9</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Levy</surname>
<given-names>Deborah L.</given-names>
</name>
<xref ref-type="aff" rid="AF0005"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="AF0010"><sup>10</sup>
</xref>
<xref ref-type="corresp" rid="c2"><sup>11</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lin</surname>
<given-names>Zhicheng</given-names>
</name>
<xref ref-type="corresp" rid="c1">*</xref>
<xref ref-type="aff" rid="AF0004"><sup>4</sup>
</xref>
<xref ref-type="aff" rid="AF0005"><sup>5</sup>
</xref>
<xref ref-type="corresp" rid="c2"><sup>11</sup>
</xref>
</contrib>
<aff id="AF0001"><sup>1</sup>
<institution>Neurogenetics Section, Neuroscience Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health</institution>
,<addr-line>Toronto, Ontario</addr-line>
,<country>Canada</country>
;</aff>
<aff id="AF0002"><sup>2</sup>
<institution>Department of Psychiatry, University of Toronto</institution>
,<addr-line>Toronto, Ontario</addr-line>
,<country>Canada</country>
;</aff>
<aff id="AF0003"><sup>3</sup>
<institution>Institute of Medical Science, University of Toronto</institution>
,<addr-line>Toronto, Ontario</addr-line>
,<country>Canada</country>
;</aff>
<aff id="AF0004"><sup>4</sup>
<institution>Laboratory of Psychiatric Neurogenomics, McLean Hospital</institution>
,<addr-line>Belmont, MA</addr-line>
;</aff>
<aff id="AF0005"><sup>5</sup>
<institution>Department of Psychiatry, Harvard Medical School</institution>
,<addr-line>Boston, MA</addr-line>
;</aff>
<aff id="AF0006"><sup>6</sup>
<institution>Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology</institution>
,<addr-line>Wuhan</addr-line>
,<country>China</country>
;</aff>
<aff id="AF0007"><sup>7</sup>
<institution>Institute of Psychiatry, Tianjin Mental Health Center</institution>
,<addr-line>Tianjin</addr-line>
,<country>China</country>
;</aff>
<aff id="AF0008"><sup>8</sup>
<institution>School of Life Science, Beijing Institute of Technology</institution>
,<addr-line>Beijing</addr-line>
,<country>China</country>
;</aff>
<aff id="AF0009"><sup>9</sup>
<institution>Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami</institution>
,<addr-line>Miami, FL</addr-line>
;</aff>
<aff id="AF0010"><sup>10</sup>
<institution>Psychology Research Laboratory, McLean Hospital</institution>
,<addr-line>Belmont, MA</addr-line>
</aff>
</contrib-group>
<author-notes><corresp id="c2"><sup>11</sup>
Joint last author.</corresp>
<corresp id="c1">*To whom correspondence should be addressed; McLean Hospital Mailstop 318, 115 Mill Street, Belmont, MA 02478, US; tel: <phone>617-855-2175</phone>
, fax: 617-855-3479, e-mail: <email>zhicheng_lin@hms.harvard.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="ppub"><month>5</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="epub"><day>26</day>
<month>12</month>
<year>2015</year>
</pub-date>
<volume>42</volume>
<issue>3</issue>
<fpage>772</fpage>
<lpage>781</lpage>
<permissions><copyright-statement>© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com</copyright-statement>
<copyright-year>2015</copyright-year>
</permissions>
<abstract><p><italic>SLC6A3</italic>
, which encodes the primary regulator of extracellular dopamine (DA) concentration, the DA transporter, has been implicated in schizophrenia (SCZ). However, the details of its genetic effect on risk remain largely unknown. The purpose of this candidate gene study was to identify a specific <italic>SLC6A3</italic>
activity associated with SCZ by using functional genetic approaches. We first examined gene activity in DA neurons isolated from case-control postmortem nigral tissue and found that the average <italic>SLC6A3</italic>
mRNA level in controls was only 0.37-fold of that in cases (<italic>P</italic>
= .0034). To understand this expression difference, we examined the association of 10 genetic markers, mostly located in the promoter region, with SCZ in 1717 subjects collected from Toronto and McLean cohorts, including 881 controls and 836 cases and identified the 5′ promoter SNP rs1478435 as having a significant association signal (uncorrected <italic>P</italic>
value: .00462; adjusted <italic>P</italic>
value: .0319) in unrelated Caucasians. Allele T was over-represented in controls (OR = .75); T-carrier controls had decreased mRNA levels in nigral DA neurons, contributing to the reduced activity in the controls. In vitro functional analysis confirmed that T carriers displayed attenuated enhancement of promoter activity. These findings collectively suggest that increased nigral <italic>SLC6A3</italic>
activity may be a risk factor for SCZ, and may help to explain high rates of comorbidity with substance abuse.</p>
</abstract>
<kwd-group><title>Key words:</title>
<kwd>dopamine neurons</kwd>
<kwd>functional genetics</kwd>
<kwd>gene expression</kwd>
<kwd>human postmortem midbrain</kwd>
<kwd>promoter function</kwd>
</kwd-group>
<counts><page-count count="10"></page-count>
</counts>
</article-meta>
</front>
</pmc>
</record>
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