Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia

Ikwunga Wonodi, L. Elliot Hong, O. Colin Stine, Braxton D. Mitchell, Amie Elliott, Rosalinda C. Roberts, Robert R. Conley, Robert P. McMahon, Gunvant K. Thaker

Research output: Contribution to journalArticlepeer-review

Abstract

Smooth pursuit eye movement (SPEM) deficit is an established schizophrenia endophenotype with a similar neurocognitive construct to working memory. Frontal eye field (FEF) neurons controlling SPEM maintain firing when visual sensory information is removed, and their firing rates directly correlate with SPEM velocity. We previously demonstrated a paradoxical association between a functional polymorphism of dopamine signaling (COMT gene) and SPEM. Recent evidence implicates the dopamine transporter gene (DAT1) in modulating cortical dopamine and associated neurocognitive functions. We hypothesized that DAT1 10/10 genotype, which reduces dopamine transporter expression and increases extracellular dopamine, would affect SPEM. We examined the effects of DAT1 genotype on: Clinical diagnosis in the study sample (n = 418; 190 with schizophrenia), SPEM measures in a subgroup with completed oculomotor measures (n = 200; 87 schizophrenia), and DAT1 gene expression in FEF tissue obtained from postmortem brain samples (n = 32; 16 schizophrenia). DAT1 genotype was not associated with schizophrenia. DAT1 10/10 genotype was associated with better SPEM in healthy controls, intermediate SPEM in unaffected first-degree relatives of schizophrenia subjects, and worse SPEM in schizophrenia subjects. In the gene expression study, DAT1 10/10 genotype was associated with significantly reduced DAT1 mRNA transcript in FEF tissue from healthy control donors (P<0.05), but higher expression in schizophrenia donors. Findings suggest regulatory effects of another gene(s) or etiological factor in schizophrenia, which modulate DAT1 gene function.

Original languageEnglish (US)
Pages (from-to)282-289
Number of pages8
JournalAmerican Journal of Medical Genetics - Neuropsychiatric Genetics
Volume150
Issue number2
DOIs
StatePublished - Mar 5 2009
Externally publishedYes

Keywords

  • DAT1 gene
  • Endophenotype
  • Expression
  • Schizophrenia

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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