The Disrupted-in-Schizophrenia-1 Ser704Cys polymorphism and brain neurodevelopmental markers in schizophrenia and healthy subjects

https://doi.org/10.1016/j.pnpbp.2014.07.005Get rights and content

Highlights

  • The DISC1 genotype effect on neurodevelopmental markers was examined using MRI.

  • The subjects were schizophrenia patients and healthy controls.

  • The genotype affected the CSP and gyral pattern predominantly in healthy controls.

  • The DISC1 genotype did not affect the adhesio interthalamica or olfactory sulcus.

  • The genotype alone cannot explain the neurodevelopmental pathology of schizophrenia.

Abstract

Increasing evidence has implicated the role of Disrupted-in-Schizophrenia-1 (DISC1), a potential susceptibility gene for schizophrenia, in early neurodevelopmental processes. However, the effect of its genotype variation on brain morphologic changes related to neurodevelopmental abnormalities in schizophrenia remains largely unknown. This magnetic resonance imaging study examined the association between DISC1 Ser704Cys polymorphism and a range of brain neurodevelopmental markers [cavum septi pellucidi (CSP), adhesio interthalamica (AI), olfactory sulcus depth, and sulcogyral pattern (Types I, II, III, and IV) in the orbitofrontal cortex (OFC)] in an all Japanese sample of 75 schizophrenia patients and 87 healthy controls. The Cys carriers had significantly larger CSP than the Ser homozygotes for both schizophrenia patients and healthy controls. The Cys carriers also exhibited a reduction in the Type I pattern of the right OFC in the healthy controls, but not in the schizophrenia patients. The DISC1 Ser704Cys polymorphism did not affect the AI and olfactory sulcus depth in either group. These results suggested a possible role of the DISC1 genotype in the early neurodevelopment of human brains, but failed to show its specific role in the neurodevelopmental pathology of schizophrenia.

Introduction

The Disrupted-in-Schizophrenia-1 (DISC1) gene, one of the candidates for a schizophrenia-susceptibility gene (Millar et al., 2000, St Clair et al., 1990), is thought to be involved in neurodevelopment and synaptic plasticity within various brain areas (Austin et al., 2003, Meyer and Morris, 2008, Schurov et al., 2004). In addition to the possible genotype effect of a functional single nucleotide polymorphism (SNP) on exon 11 (rs821616, a serine to cysteine substitution at codon 704) on brain morphology and function in healthy subjects (Callicott et al., 2005, Hashimoto et al., 2006, Li et al., 2013, Thomson et al., 2005), our preliminary study suggested that it might differentially affect the gray matter volume of the neocortical and limbic regions in schizophrenia patients and healthy controls (Takahashi et al., 2009). Although recent whole-brain gray matter analysis using voxel-based morphometry (VBM) failed to replicate our earlier findings (Kido et al., in press), the possibility still exists that its genotype variation is specifically related to brain morphologic changes that are closely related to abnormal early neurodevelopment in schizophrenia.

Several magnetic resonance imaging (MRI) studies of potential ‘brain neurodevelopmental markers’ have implicated the role of aberrant neurodevelopmental processes in the pathophysiology of schizophrenia (Pantelis et al., 2005). For example, a large cavum septi pellucidi (CSP), which is formed by the incomplete fusion of the septum pellucidum (Rakic and Yakovlev, 1968), may be related to fetal neurodevelopmental abnormalities of the corpus callosum and limbic structures in schizophrenia (Trzesniak et al., 2011b). While our previous MRI study showed no difference in the size and prevalence of CSP in a large sample of schizophrenia patients compared with controls (Takahashi et al., 2007), a recent meta-analysis suggested that a large CSP was more common in schizophrenia (Trzesniak et al., 2011b). The adhesio interthalamica (AI), a narrow bridge connecting the medial surfaces of the thalami, is variable in size among individuals and missing in about 20% of human brains (Rosales et al., 1968). Previous neuroimaging studies have demonstrated that schizophrenia patients are more likely to have a smaller AI (Takahashi et al., 2008, Trzesniak et al., 2011a), possibly reflecting early developmental abnormalities. In addition to these neurodevelopmental markers located in the midline brain regions, gross morphologic changes of the orbitofrontal cortex (OFC) in schizophrenia (Nakamura et al., 2007, Takahashi et al., 2013a, Takayanagi et al., 2010) are likely to reflect abnormal neurodevelopment during the gestational period.

Altered OFC patterns (Chakirova et al., 2010) and abnormal CSP (Choi et al., 2008) in subjects at high genetic risk of schizophrenia may support a genetic influence on such gross morphologic changes in schizophrenia. Furthermore, since recent animal data (Osbun et al., 2011, Shen et al., 2008) as well as genetic analyses in patients with callosal agenesis (Osbun et al., 2011) suggest a crucial role for DISC1 in callosal development, it is possible that its genotype variation may influence the size of CSP. However, VBM approach which we used to explore the genotype effect of DISC1 on brain morphology (Kido et al., in press) cannot examine the gross brain characteristics. It thus remains largely unknown as to whether DISC1 genotype could influence the CSP and other neurodevelopmental markers in patients with schizophrenia as well as in healthy subjects.

In this MRI study, we aimed to investigate the effects of DISC1 Ser704Cys SNP on a range of neurodevelopmental markers in schizophrenia patients and matched healthy controls. On the basis of previous MRI observations in schizophrenia, we selected the size and prevalence of CSP and AI (Trzesniak et al., 2011a, Trzesniak et al., 2011b), depth of the olfactory sulcus (Takahashi et al., 2013a), and the OFC sulcogyral pattern (Nakamura et al., 2007) as possible neurodevelopmental markers. Despite evidence implicating the role of DISC1 in early neurodevelopmental processes of human brains, there have also been questions about DISC1 as a genetic risk factor of schizophrenia (Sullivan, 2013). We therefore predicted that variation in the DISC1 genotype could be related to the morphology of these structures regardless of diagnosis, but we also explored its specific role in the gross brain abnormalities of schizophrenia.

Section snippets

Subjects

Seventy-five patients with schizophrenia (41 males and 34 females; mean age = 27.4 years, SD = 6.1) who met the ICD-10 research criteria (World health organization, 1993) were recruited from the inpatient and outpatient clinics of the Department of Neuropsychiatry of Toyama University Hospital. The patients were diagnosed following a structured clinical interview by psychiatrists using the Comprehensive Assessment of Symptoms and History (CASH; Andreasen et al., 1992). Clinical symptoms were rated

Sample characteristics and genotyping results

The two groups were matched for age, height, sex, and parental education, but the controls had attained a higher level of education than the schizophrenia patients. Clinical or demographic data did not differ between the Ser homozygotes and Cys carriers in the schizophrenia and control groups (Table 1). There were two Cys homozygotes in the current sample (one male patient and one male control). The observed genotype frequency was within the distribution expected according to the HWE. The

Discussion

To our knowledge, this is the first MRI study to report the genotype effect of DISC1 Ser704Cys SNP on several brain morphologic characteristics closely related to early neurodevelopment in both schizophrenia and healthy comparisons. The subjects carrying the Cys allele, which may increase the susceptibility to schizophrenia (Qu et al., 2007), had a significantly larger size and higher prevalence of CSP (≥ 1 slice) than the Ser homozygotes regardless of diagnosis. The Cys carriers also exhibited

Conclusion

This preliminary study suggested that genotype variation in DISC1 may be related to the normal development of the midline brain region and cortical folding in the OFC. However, we did not observe a genotype effect of DISC1 on possible neurodevelopmental markers specific to schizophrenia, suggesting the role of other genetic and/or environmental factors in the development of gross morphologic abnormalities in schizophrenia.

Acknowledgments

This research was supported in part by Grants-in-Aid for Scientific Research (C) (Nos. 22591275, 24591699, and 26461739) and Grant-in-Aid for Scientific Research (B) (No. 24390281) from the Japanese Society for the Promotion of Science, Health and Labour Sciences Research Grants (Comprehensive Research on Disability, Health and Welfare, H23-Seishin-Ippan-002 and H23-Seishin-Ippan-009), a Research Grant from the JSPS Asian Core Program, and a Grant from Research Group for Schizophrenia, Japan.

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