Elsevier

Biological Psychiatry

Volume 65, Issue 6, 15 March 2009, Pages 535-540
Biological Psychiatry

Research Report
A Neuregulin 1 Variant Is Associated with Increased Lateral Ventricle Volume in Patients with First-Episode Schizophrenia

https://doi.org/10.1016/j.biopsych.2008.10.020Get rights and content

Background

Structural brain abnormalities are already present at early phases of psychosis and might be the consequence of neurodevelopmental deviance. Neuregulin 1 gene (NRG1) is a candidate gene for schizophrenia, and its protein has different roles in nervous system development and plasticity. A single nucleotide polymorphism (SNP) within NRG1, SNP8NRG243177, has been associated with brain function among healthy and high-risk subjects and with reduced cell migration among patients with schizophrenia. We examined whether variations in this polymorphism influence brain volumes in first-episode schizophrenia subjects.

Methods

Ninety-five minimally medicated patients experiencing their first episode of schizophrenia underwent genotyping of three SNPs within the NRG1 gene and structural brain magnetic resonance imaging (MRI). A comparison of volumes of lobar gray matter (GM), lateral ventricles, and cortical cerebrospinal fluid (CSF) was made between the groups according to their genotype after controlling for total intracranial volume.

Results

The SNP8NRG243177 risk T allele was significantly associated, in an allele copy number-dependent fashion, with increased lateral ventricle volume. Genotype explained 7% of the variance of lateral ventricle volume. No significant differences in GM lobar or cortical CSF volumes were found among subgroups.

Conclusions

Our findings suggest that genetic variations of the NRG1 gene can contribute to the enlargement of the lateral ventricles described in early phases of schizophrenia. These results suggest novel lines of research into potential mechanisms by which schizophrenia susceptibility genes might exert their effect on brain structure.

Section snippets

Subjects

The subjects formed part of a large prospective longitudinal study on first-episode nonaffective psychosis (Programa Asistencial Fases Iniciales de Psicosis [PAFIP]) (32). Only those patients with a DSM-IV diagnosis of schizophrenia 6 months after inclusion who had had genomic DNA extracted and had undergone MRI scans were included in this study (n = 95). Gender distribution was 59 male subjects (62.1%) and 36 female subjects (37.9%). Mean age of onset in our sample was 27.7 years (SD = 7.9),

Results

The number of patients from each genotype group did not significantly deviate from Hardy-Weinberg equilibrium for any of the three SNPs. The comparisons across the three genotype groups of SNP8NRG243177 among patients regarding sociodemographic and clinical characteristics are presented in Table 1, showing that these groups did not significantly differ in any of the variables, including symptom severity. Intracranial volume showed a highly significant correlation with lateral ventricle volumes

Discussion

We found a significant association between lateral ventricle volume and the NRG1 SNP8NRG243177, whereby those patients carrying the at-risk T allele/s presented substantially enlarged lateral ventricles, and this occurred in an allele copy number-dependent fashion (Figure 1). Carriers of the T allele had a 31.3% greater volume of lateral ventricles than patients homozygous for the C allele. Interestingly, patients homozygous for the C allele had a lateral ventricle volume similar to that of the

References (46)

  • N.C. Stefanis et al.

    Impact of schizophrenia candidate genes on schizotypy and cognitive endophenotypes at the population level

    Biol Psychiatry

    (2007)
  • B. Crespo-Facorro et al.

    Low-activity allele of catechol-O-methyltransferase (COMTL) is associated with increased lateral ventricles in patients with first episode non-affective psychosis

    Prog Neuropsychopharmacol Biol Psychiatry

    (2007)
  • B. Crespo-Facorro et al.

    Reduced thalamic volume in first-episode non-affective psychosis: Correlations with clinical variables, symptomatology and cognitive functioning

    Neuroimage

    (2007)
  • C. Rio et al.

    Neuregulin and erbB receptors play a critical role in neuronal migration

    Neuron

    (1997)
  • G. Lopez-Bendito et al.

    Tangential neuronal migration controls axon guidance: A role for neuregulin-1 in thalamocortical axon navigation

    Cell

    (2006)
  • S.Y. Zhou et al.

    Decreased volume and increased asymmetry of the anterior limb of the internal capsule in patients with schizophrenia

    Biol Psychiatry

    (2003)
  • A.M. McIntosh et al.

    White matter density in patients with schizophrenia, bipolar disorder and their unaffected relatives

    Biol Psychiatry

    (2005)
  • S.M. Lawrie et al.

    Brain abnormality in schizophreniaA systematic and quantitative review of volumetric magnetic resonance imaging studies

    Br J Psychiatry

    (1998)
  • I.C. Wright et al.

    Meta-analysis of regional brain volumes in schizophrenia

    Am J Psychiatry

    (2000)
  • D. Fannon et al.

    Third ventricle enlargement and developmental delay in first-episode psychosis: Preliminary findings

    Br J Psychiatry

    (2000)
  • N.C. Andreasen et al.

    Ventricular enlargement in schizophrenia: Relationship to positive and negative symptoms

    Am J Psychiatry

    (1982)
  • C. McDonald et al.

    Brain volumes in familial and non-familial schizophrenic probands and their unaffected relatives

    Am J Med Genet

    (2002)
  • C. McDonald et al.

    Regional brain morphometry in patients with schizophrenia or bipolar disorder and their unaffected relatives

    Am J Psychiatry

    (2006)
  • Cited by (0)

    View full text