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Open Access Study protocol

NPAS3 variants in schizophrenia: a neuroimaging study

Denise Bernier1*, Georgina Macintyre2, Robert Bartha3, Christopher C Hanstock4, David McAllindon1, Diane Cox2, Scot Purdon5, Katherine J Aitchison6, Benjamin Rusak7 and Philip G Tibbo1

Author Affiliations

1 Department of Psychiatry, Dalhousie University, Halifax, Canada

2 Department of Medical Genetics, University of Alberta, Edmonton, Canada

3 Department of Diagnostic Radiology and Nuclear Medicine, Robarts Research Institute, University of Western Ontario, London, Canada

4 Department of Biomedical Engineering, University of Alberta, Edmonton, Canada

5 Department of Psychiatry, University of Alberta, Edmonton, Canada

6 Departments of Psychiatry and Medical Genetics, University of Alberta, Edmonton, Canada

7 Departments of Psychiatry, Psychology and Pharmacology, Dalhousie University, Halifax, Canada

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BMC Medical Genetics 2014, 15:37  doi:10.1186/1471-2350-15-37

Published: 27 March 2014

Abstract

Background

This research is a one-site neuroimaging component of a two-site genetic study involving patients with schizophrenia at early and later stages of illness. Studies support a role for the neuronal Per-Arnt-Sim 3 (NPAS3) gene in processes that are essential for normal brain development. Specific NPAS3 variants have been observed at an increased frequency in schizophrenia. In humans, NPAS3 protein was detected in the hippocampus from the first trimester of gestation. In addition, NPAS3 protein levels were reduced in the dorsolateral prefrontal cortex of some patients with schizophrenia. Npas3 knockout mice display behavioural, neuroanatomical and structural changes with associated severe reductions in neural precursor cell proliferation in the hippocampal dentate gyrus. This study will evaluate the hypothesis that the severe reductions in neural precursor cell proliferation in the dentate gyrus will be present to some degree in patients carrying schizophrenia-associated NPAS3 variants and less so in other patients.

Methods/Design

Patients enrolled in the larger genetic study (n = 150) will be invited to participate in this neuroimaging arm. The genetic data will be used to ensure a sample size of 45 participants in each genetic subgroup of patients (with and without NPAS3 variants). In addition, we will recruit 60 healthy controls for acquisition of normative data. The following neuroimaging measures will be acquired from the medial temporal region: a) an index of the microcellular environment; b) a macro-structural volumetric measure of the hippocampus; and c) concentration levels of N-acetylaspartate, a marker of neuronal health.

Discussion

This study will help to establish the contribution of the NPAS3 gene and its variants to brain tissue abnormalities in schizophrenia. Given the genetic and phenotypic heterogeneity of the disorder and the large variation in outcomes, the identification of biological subgroups may in future support tailoring of treatment approaches in order to optimize recovery.

Keywords:
Relaxation time constants; 1H-MRS; N-acetylaspartate; Hippocampus; Temporal lobe; Psychosis; Genetics