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Effects of ZNF804A on neurophysiologic measures of cognitive control

Molecular Psychiatry volume 18, pages 852–854 (2013)Cite this article

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Schizophrenia has heritability estimates of 70–85%1 and genetic risk in most cases is presumably a result of multiple genetic loci of small effect. In recent years, genome-wide association studies have facilitated the discovery of potential risk genes for neuropsychiatric disorders. ZNF804A rs1344706 was the first single-nucleotide polymorphism (A/C, A=risk allele) to show a significant association with schizophrenia in genome-wide association studies (P=1.6 × 10−7).2 Although the physiological function of ZNF804A and its role in schizophrenia risk is currently unclear, the gene has been shown to be associated with psychosis,3 and several potential intermediate biological phenotypes, such as deficits in executive function4 and altered cortical connectivity during working memory5, 6 and theory of mind.7

Cognitive deficits in schizophrenia are broad and conspicuously include deficits in cognitive control, an executive function that refers to the ability to direct behavior toward a goal in the presence of conflict. Studies have shown altered function and connectivity of the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in patients with schizophrenia during cognitive control tasks.8 Recently, these alterations have been suggested to represent an intermediate phenotype because they are also found in healthy siblings of patients with schizophrenia.9, 10 In this study, we aimed to explore the role of ZNF804A rs1344706 on activation and functional connectivity measures related to cognitive control. To this end, we used the Modified Flanker task that includes response inhibition (RI) and interference monitoring and suppression (IMS), two important components of cognitive control function. A total of 208 Caucasian healthy volunteers with no history of psychosis and no first-degree relatives with a schizophrenia spectrum disorder and with good quality functional magnetic resonance imaging (fMRI) data and genotype information for ZNF804A rs1344706 were selected from the larger sample of the Clinical Brain Disorders Branch Sibling Study of schizophrenia at the National Institute of Mental Health (DR Weinberger PI). In all, 89 subjects were rs1344706 AA homozygotes, 93 were rs1344706 AC heterozygotes and 26 were rs1344706 CC homozygotes. The genotype groups did not differ across demographic and task performance variables based on ANOVA and chi-square analyses (see Supplementary Materials, Supplementary Table 1).

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institute of Mental Health, NIH, Bethesda, MD 20892, USA.

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Authors and Affiliations

  1. Genes, Cognition, and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, USA

    K Thurin, R Rasetti, F Sambataro, M Safrin, Q Chen, J H Callicott, V S Mattay & D R Weinberger

  2. Brain Center for Motor and Social Cognition, Istituto Italiano di Tecnologia@UNIPr, Parma, Italy

    F Sambataro

  3. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA

    Q Chen, V S Mattay & D R Weinberger

Authors
  1. K Thurin
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  2. R Rasetti
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  3. F Sambataro
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  4. M Safrin
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  5. Q Chen
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  6. J H Callicott
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  8. D R Weinberger
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Correspondence to D R Weinberger.

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Thurin, K., Rasetti, R., Sambataro, F. et al. Effects of ZNF804A on neurophysiologic measures of cognitive control. Mol Psychiatry 18, 852–854 (2013). https://doi.org/10.1038/mp.2012.134

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