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Neural effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253

Authors

  • Emma J. Rose,

    1. Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, St. James Hospital, Dublin, Ireland
    2. Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
    Current affiliation:
    1. Transdisciplinary Science and Translational Prevention Program, Molecular Epidemiology, Genomics, Environment & Health, RTI International, Baltimore, Maryland
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  • Derek W. Morris,

    1. Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, St. James Hospital, Dublin, Ireland
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  • April Hargreaves,

    1. Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, St. James Hospital, Dublin, Ireland
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  • Ciara Fahey,

    1. Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, St. James Hospital, Dublin, Ireland
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  • Ciara Greene,

    1. Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, St. James Hospital, Dublin, Ireland
    2. Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
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  • Hugh Garavan,

    1. Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
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  • Michael Gill,

    1. Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, St. James Hospital, Dublin, Ireland
    2. Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
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  • Aiden Corvin,

    1. Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, St. James Hospital, Dublin, Ireland
    2. Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
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  • Gary Donohoe

    Corresponding author
    1. Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
    • Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, St. James Hospital, Dublin, Ireland
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  • All authors confirm that they have no conflict of interest in relation to this manuscript.

Correspondence to:

Gary Donohoe, D.Clin.Psych., Ph.D., Assoc. Prof. of Clinical Psychology and Neuropsychology, Trinity College Dublin, The Trinity Center, St. James's Hospital, Dublin 8, Ireland.

E-mail: gary.donohoe@tcd.ie

ABSTRACT

The single nucleotide polymorphism rs10503253 within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2 has been identified as genome-wide significant for schizophrenia (SZ). This gene is of unknown function but has been implicated in multiple neurodevelopmental disorders that impact upon cognition, leading us to hypothesize that an effect on brain structure and function underlying cognitive processes may be part of the mechanism by which CMSD1 increases illness risk. To test this hypothesis, we investigated this CSMD1 variant in vivo in healthy participants in a magnetic resonance imaging (MRI) study comprised of both fMRI of spatial working memory (N = 50) and a voxel-based morphometry investigation of grey and white matter (WM) volume (N = 150). Analyses of these data indicated that the risk “A” allele was associated with comparatively reduced cortical activations in BA18, that is, middle occipital gyrus and cuneus; posterior brain regions that support maintenance processes during performance of a spatial working memory task. Conversely, there was an absence of significant structural differences in brain volume (i.e., grey or WM). In accordance with previous evidence, these data suggest that CSMD1 may mediate brain function related to cognitive processes (i.e., executive function); with the relatively deleterious effects of the identified “A” risk allele on brain activity possibly constituting part of the mechanism by which CSMD1 increases schizophrenia risk. © 2013 Wiley Periodicals, Inc.

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