Progress in Neuro-Psychopharmacology and Biological Psychiatry
The Disrupted-in-Schizophrenia-1 Ser704Cys polymorphism and brain neurodevelopmental markers in schizophrenia and healthy subjects
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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2021, Translational Research in AnatomyCitation Excerpt :An association was found between the decreased expression of Type I and increased expression of Type III in carriers of the gene, however this was only found in the control group (those who did not develop schizophrenia). This is similar to previous research of a different single nucleotide polymorphism of the DISC1 gene (YWHAE), where a C allele is protective and a G allele a risk factor for schizophrenia [32]. Similarly, decreased expression of Type I and increased expression of Type III was found in individuals with the risk allele, but only in the control sample.
The interaction of NOS1AP, DISC1, DAOA, and GSK3B confers susceptibility of early-onset schizophrenia in Chinese Han population
2018, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Lepagnol-Bestel et al. (2010) found that the DISC1 gene is associated with the negative dimension of SCZ. However, some studies did not identify an association in Japanese, American, and Korean samples (Ratta-Apha et al., 2013; Hotta et al., 2011; Docherty et al., 2014; Bae et al., 2013; Mathieson et al., 2012; Takahashi et al., 2015; Prata et al., 2011). Recently, many studies (Ma et al., 2009; Müller et al., 2011) have reported that the DAOA gene locus is involved in conferring susceptibility to SCZ.
Gene polymorphisms of DISC1 is associated with schizophrenia: Evidence from a meta-analysis
2018, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :This conclusion was based on the result that the risk allele A carriers of DISC1 variant (rs821579) had higher gray matter density in regional left parahippocampal gyrus and right orbitofrontal cortex in SCZ patients, but had decreased gray matter density of these brain regions in healthy controls (Wei et al., 2012). However, DISC1 polymorphisms (rs821616) did not present its specific role in the neurodevelopmental pathology of SCZ for the Cys carriers showed a reduction in the Type I pattern of the right orbitofrontal cortex in the healthy controls, but not in the SCZ patients in Japanese population (Takahashi et al., 2015). Besides that, there was no significant effect of Cys704Ser on prefrontal cortical function of SCZ patients in the Caucasians (Prata et al., 2011).
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2017, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :The OFC classification method used in this study is both valid and reliable, and minimally affected by confounders including gender differences and imaging sites. In support of the reliability of our OFC classification, the percentage distribution of OFC pattern found in our sample (Type I:II:III = 49:19:32%) was similar to that of previously examined samples of healthy controls (aggregated means of Type I:II:III = 60:19:20%; χ2(2) = 4.32, p = 0.12) (Bartholomeusz et al., 2013; Chakirova et al., 2010; Chiavaras and Petrides, 2000; Cropley et al., 2015; Ganella et al., 2015; Isomura et al., 2017; Lavoie et al., 2014; Nakamura et al., 2007; Nishikawa et al., 2015; Takahashi et al., 2014, 2015; Takayanagi et al., 2010; Uehara-Aoyama et al., 2011; Watanabe et al., 2014; Whittle et al., 2014). We also did not find any gender-related differences in OFC pattern distribution, consistent with most previous studies (Uehara-Aoyama et al., 2011; Whittle et al., 2014).