Increased nigral SLC6A3 activity in schizophrenia patients: Findings from the Toronto-McLean Cohorts

James L. Kennedy, Nian Xiong, Jinlong Yu, Clement C. Zai, Jennie G. Pouget, Jie Li, Kefu Liu, Hong Qing, Tao Wang, Eden Martin, Deborah L. Levy, Zhicheng Lin

Research output: Contribution to journalArticle

6 Scopus citations

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 specific SLC6A3 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 SLC6A3 mRNA 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 (uncorrected P value:. 00462; adjusted P 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 SLC6A3 activity may be a risk factor for SCZ, and may help to explain high rates of comorbidity with substance abuse.

Original languageEnglish (US)
Pages (from-to)772-781
Number of pages10
JournalSchizophrenia bulletin
Volume42
Issue number3
DOIs
StatePublished - May 1 2016

Keywords

  • dopamine neurons
  • functional genetics
  • gene expression
  • human postmortem midbrain
  • promoter function

ASJC Scopus subject areas

  • Psychiatry and Mental health

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    Kennedy, J. L., Xiong, N., Yu, J., Zai, C. C., Pouget, J. G., Li, J., Liu, K., Qing, H., Wang, T., Martin, E., Levy, D. L., & Lin, Z. (2016). Increased nigral SLC6A3 activity in schizophrenia patients: Findings from the Toronto-McLean Cohorts. Schizophrenia bulletin, 42(3), 772-781. https://doi.org/10.1093/schbul/sbv191