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Polymorphism in the ZNF804A Gene and Variation in D1 and D2/D3 Dopamine Receptor Availability in the Healthy Human Brain: A Dual Positron Emission Tomography Study

  • Catherine E. Hegarty
    Affiliations
    Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland

    Neuroscience Graduate Program, Brown University, Providence, Rhode Island
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  • Angela M. Ianni
    Affiliations
    Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
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  • Philip D. Kohn
    Affiliations
    Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
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  • Bhaskar Kolachana
    Affiliations
    Human Brain Collection Core, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
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  • Michael Gregory
    Affiliations
    Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
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  • Joseph C. Masdeu
    Affiliations
    Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
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  • Author Footnotes
    1 DPE and KFB contributed equally to this work.
    Daniel P. Eisenberg
    Footnotes
    1 DPE and KFB contributed equally to this work.
    Affiliations
    Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
  • Author Footnotes
    1 DPE and KFB contributed equally to this work.
    Karen F. Berman
    Correspondence
    Address correspondence to Karen F. Berman, M.D.
    Footnotes
    1 DPE and KFB contributed equally to this work.
    Affiliations
    Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
  • Author Footnotes
    1 DPE and KFB contributed equally to this work.
Published:December 21, 2020DOI:https://doi.org/10.1016/j.bpsc.2020.12.006

      Abstract

      Background

      The rs1344706 single nucleotide polymorphism in the ZNF804A gene has been associated with risk for psychosis in multiple genome-wide association studies, yet mechanisms underlying this association are not known. Given preclinical work suggesting an impact of ZNF804A on dopamine receptor gene transcription and clinical studies establishing dopaminergic dysfunction in patients with schizophrenia, we hypothesized that the ZNF804A risk single nucleotide polymorphism would be associated with variation in dopamine receptor availability in the human brain.

      Methods

      In this study, 72 healthy individuals genotyped for rs1344706 completed both [18F]fallypride and [11C]NNC-112 positron emission tomography scans to measure D2/D3 and D1 receptor availability, respectively. Genetic effects on estimates of binding potential for each ligand were tested first with canonical subject-specific striatal regions of interest analyses, followed by exploratory whole-brain voxelwise analyses to test for more localized striatal signals and for extrastriatal effects.

      Results

      Region of interest analyses revealed significantly less D2/D3 receptor availability in risk-allele homozygotes (TT) compared with non-risk allele carriers (G-allele carrier group: TG and GG) in the associative striatum and sensorimotor striatum, but no significant differences in striatal D1 receptor availability.

      Conclusions

      These data suggest that ZNF804A genotype may be meaningfully linked to dopaminergic function in the human brain. The results also may provide information to guide future studies of ZNF804A-related mechanisms of schizophrenia risk.

      Keywords

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