title: Increased Nigral SLC6A3 Activity in Schizophrenia Patients: Findings From the Toronto-McLean Cohorts.
abstract: SLC6A3, 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 specificSLC6A3activity 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 averageSLC6A3mRNA level in controls was only 0.37-fold of that in cases (P= .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 (uncorrectedPvalue: .00462; adjustedPvalue: .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 nigralSLC6A3activity may be a risk factor for SCZ, and may help to explain high rates of comorbidity with substance abuse.
authors.affiliation: Neurogenetics Section, Neuroscience Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada;
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
authors.affiliation: Laboratory of Psychiatric Neurogenomics, McLean Hospital, Belmont, MA; Department of Psychiatry, Harvard Medical School, Boston, MA; Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;
authors.forename: Nian
authors.initials: N
authors.lastname: Xiong
authors.affiliation: Laboratory of Psychiatric Neurogenomics, McLean Hospital, Belmont, MA; Department of Psychiatry, Harvard Medical School, Boston, MA;
authors.forename: Jinlong
authors.initials: J
authors.lastname: Yu
authors.affiliation: Neurogenetics Section, Neuroscience Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Clement C
authors.initials: CC
authors.lastname: Zai
authors.affiliation: Neurogenetics Section, Neuroscience Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Jennie G
authors.initials: JG
authors.lastname: Pouget
authors.affiliation: Laboratory of Psychiatric Neurogenomics, McLean Hospital, Belmont, MA; Department of Psychiatry, Harvard Medical School, Boston, MA; Institute of Psychiatry, Tianjin Mental Health Center, Tianjin, China;
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory of Psychiatric Neurogenomics, McLean Hospital, Belmont, MA; Department of Psychiatry, Harvard Medical School, Boston, MA; School of Life Science, Beijing Institute of Technology, Beijing, China;
authors.forename: Kefu
authors.initials: K
authors.lastname: Liu
authors.affiliation: School of Life Science, Beijing Institute of Technology, Beijing, China;
authors.forename: Hong
authors.initials: H
authors.lastname: Qing
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL;
authors.forename: Eden
authors.initials: E
authors.lastname: Martin
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA; Psychology Research Laboratory, McLean Hospital, Belmont, MA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Levy
authors.affiliation: Laboratory of Psychiatric Neurogenomics, McLean Hospital, Belmont, MA; Department of Psychiatry, Harvard Medical School, Boston, MA; zhicheng_lin@hms.harvard.edu.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Lin
mesh_terms: D000328:Adult; D001900:Boston; D015331:Cohort Studies; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D009864:Ontario; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics*; D013378:Substantia Nigra / Q000378:metabolism*; D014015:Tissue Banks
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; C493214:SLC6A3 protein, human
keywords: dopamine neurons; functional genetics; gene expression; human postmortem midbrain; promoter function