CACNA1C genomewide supported psychosis genetic variation affects cortical brain white matter integrity in Chinese patients with schizophrenia.

OBJECTIVE: Recent genomewide association studies have implicated the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) genetic variant in schizophrenia, which is associated with functional brain changes and cognitive deficits in healthy individuals. However, the impact of CACNA1C on brain white matter integrity in schizophrenia remains unclear. On the basis of prior evidence of CACNA1C-mediated changes involving cortical brain regions, we hypothesize that CACNA1C risk variant rs1006737 is associated with reductions of white matter integrity in the frontal, parietal, and temporal regions and cingulate gyrus. METHOD: A total of 160 Chinese participants (96 DSM-IV-diagnosed patients with schizophrenia and 64 healthy controls) were genotyped by using blood samples and underwent structural magnetic resonance imaging and diffusion tensor imaging scans from 2008 to 2012. Two-way analysis of covariance was employed to examine CACNA1C-related genotype effects, diagnosis effects, and genotype × diagnosis interaction effects on fractional anisotropy (FA) of relevant brain regions. RESULTS: Significant diagnosis-genotype interactions were observed (left frontal lobe mean FA: F1,156 = 6.22, P = .014; left parietal lobe mean FA: F1,156 = 7.14, P = .008; left temporal lobe mean FA: F1,156 = 8.37, P = .004). Compared with patients who were A carriers, patients who were G homozygotes had lower mean FA in the left frontal lobe (F1,93 = 2.504, P = .014), left parietal lobe (F1,93 = 2.37, P = .020), and left temporal lobe (F1,93 = 3.01, P = .003), with standardized effect sizes of -1.43, -1.3, and -1.0, respectively. CONCLUSIONS: CACNA1C risk variant rs1006737 affects cortical white matter integrity in schizophrenia. Further imaging genetic investigations on the mediating effect of CACNA1C in schizophrenia can uncover brain circuitries involved in schizophrenia and suggest potential novel targets for intervention.

Corpus callosum morphology in first-episode and chronic schizophrenia: combined magnetic resonance and diffusion tensor imaging study of Chinese Singaporean patients.

BACKGROUND: Abnormalities in the corpus callosum have been reported in patients with schizophrenia for over 30 years but the influence of inter-individual differences and illness characteristics remains to be fully elucidated. AIMS: To examine the influence of individual and illness characteristics on the corpus callosum in Chinese Singaporean patients with schizophrenia. METHOD: Using magnetic resonance and diffusion tensor imaging, mean corpus callosum area, volume and fractional anisotropy were investigated in 120 Chinese Singaporean patients (52 with chronic and 68 with first-episode schizophrenia) and compared with data from 75 matched healthy controls. RESULTS: Both area and volume were significantly reduced in patients relative to controls but no significant differences in corpus callosum existed between genders in either patients or controls. Differences in area and volume of the corpus callosum were greatest in patients whose condition was chronic relative to patients with a first episode and controls. Anterior callosum in patients, regardless of chronicity, was no different to that of controls. CONCLUSIONS: Morphological abnormalities in the corpus callosum may increase with illness progression.

Genome-wide supported psychosis risk variant in ZNF804A gene and impact on cortico-limbic WM integrity in schizophrenia.

Genome-wide association, case association genetic and meta-analytic studies have highlighted ZNF804A as a robust genome-wide supported susceptibility gene for schizophrenia (SCZ). In view of the possible involvement of ZNF804A gene in early neurodevelopment and cellular processes including oligodendrocyte proliferation and differentiation, we examined the effect of ZNF804A on brain WM (WM) integrity in patients with SCZ. Based on extant data in healthy controls (HC), we hypothesized that ZNF804A risk variant rs1344706 is associated with lower fractional anisotropy (FA) in brain regions within cortico-limbic circuits, namely frontal, parietal, medial temporal lobes, and cingulate gyri in SCZ. A total of 200 Chinese participants (125 patients with DSM-IV diagnosis of SCZ and 75 controls) were genotyped using blood samples, a subset of 153 participants (89 patients with DSM-IV diagnosis of SCZ and 64 controls) underwent structural magnetic resonance imaging and diffusion tensor imaging (DTI). There are significant effects of diagnosis (left cingulate gyrus: Adjusted F(1,149) = 9.36, P = 0.003) and diagnosis-genotype interactions (left parietal lobe: Adjusted F(1,147) = 7.39, P = 0.007; right parietal lobe: Adjusted F(1,147) = 6.95, P = 0.009; right medial temporal lobe: Adjusted F(1,147) = 8.79, P = 0.004; left cingulate gyrus: Adjusted F(1,147) = 8.02, P = 0.005). Specifically, we found that patients with SCZ who are risk T homozygotes have lower FA in bilateral parietal lobes, and left cingulate gyrus compared with G carriers. Compared with risk T homozygotes in HC, patients with SCZ who are risk T homozygotes have decreased FA in bilateral parietal lobes, and left cingulate gyrus as well as right medial temporal lobe. Our findings suggest that ZNF804A risk variant influence WM integrity involving cortico-limbic brain regions in SCZ and highlight the importance of investigating the impact of genome-wide supported risk factors on intermediate phenotypes with potential to shed light on the neurobiology of SCZ.

Arcuate fasciculus abnormalities and their relationship with psychotic symptoms in schizophrenia.

Disruption of fronto-temporal connections involving the arcuate fasciculus (AF) may underlie language processing anomalies and psychotic features such as auditory hallucinations in schizophrenia. No study to date has specifically investigated abnormalities of white matter integrity at particular loci along the AF as well as its regional lateralization in schizophrenia. We examined white matter changes (fractional anisotropy (FA), axial diffusivity (AD), asymmetry indices) along the whole extent of the AF and their relationship with psychotic symptoms in 32 males with schizophrenia and 44 healthy males. Large deformation diffeomorphic metric mapping and Fiber Assignment Continuous Tracking were employed to characterize FA and AD along the geometric curve of the AF. Our results showed that patients with schizophrenia had lower FA in the frontal aspects of the left AF compared with healthy controls. Greater left FA and AD lateralization in the temporal segment of AF were associated with more severe positive psychotic symptoms such as delusions and hallucinations in patients with schizophrenia. Disruption of white matter integrity of the left frontal AF and accentuation of normal left greater than right asymmetry of FA/AD in the temporal AF further support the notion of aberrant fronto-temporal connectivity in schizophrenia. AF pathology can affect corollary discharge of neural signals from frontal speech/motor initiation areas to suppress activity of auditory cortex that may influence psychotic phenomena such as auditory hallucinations and facilitate elaboration of delusional content.

ARVCF genetic influences on neurocognitive and neuroanatomical intermediate phenotypes in Chinese patients with schizophrenia.

OBJECTIVE: There are notable similarities between velocardiofacial syndrome and schizophrenia in terms of neurocognitive deficits and brain structural abnormalities. These similarities have supported the role of the armadillo repeat gene deleted in velocardiofacial syndrome (ARVCF) as a susceptibility gene in schizophrenia. This study investigated the relationships between haplotypes of the ARVCF gene and specific intermediate phenotypes in schizophrenia. We hypothesized that ARVCF gene haplotypes influence caudate nucleus volume, fractional anisotropy, and neurocognitive functioning in schizophrenia. METHOD: Between May 2006 and November 2009, 200 Chinese participants (125 patients with DSM-IV diagnosis of schizophrenia and 75 controls) were genotyped using blood samples, and a subset of 166 participants (99 patients with DSM-IV diagnosis of schizophrenia and 67 controls) underwent structural magnetic resonance imaging, diffusion tensor imaging, and completed neuropsychological testing. RESULTS: The haplotype T-G-A-T-T-G-G-C-T-G-T (ARVCF-Hap1) was significantly associated with fractional anisotropy of the caudate nucleus and executive functioning in patients. Specifically, patients with more copies of ARVCF-Hap1 have lower white matter integrity in caudate nucleus (P = .0008) and greater perseverative errors (P = .00003) on the Wisconsin Card Sorting Test. A trend of lower caudate volume (P = .015) in patients with more copies of ARVCF-Hap1 was also observed. CONCLUSIONS: These findings are consistent with known ARVCF gene effects on neurodevelopment in terms of cellular arrangement, migration, and intracellular signaling involving the striatum and may involve interactions with other brain networks such as prefrontal cortex, and they underscore the importance of imaging-genetic studies to elucidate the genetic influences underlying intermediate phenotypes in complex neurobehavioral disorders.

Genome wide association studies (GWAS) and copy number variation (CNV) studies of the major psychoses: what have we learnt?

Schizophrenia (SZ) and bipolar disorder (BPD) have high heritabilities and are clinically and genetically complex. Genome wide association studies (GWAS) and studies of copy number variations (CNV) in SZ and BPD have allowed probing of their underlying genetic risks. In this systematic review, we assess extant genetic signals from published GWAS and CNV studies of SZ and BPD up till March 2011. Risk genes associated with SZ at genome wide significance level (p value<7.2 × 10(-8)) include zinc finger binding protein 804A (ZNF804A), major histocompatibility (MHC) region on chromosome 6, neurogranin (NRGN) and transcription factor 4 (TCF4). Risk genes associated with BPD include ankyrin 3, node of Ranvier (ANK3), calcium channel, voltage dependent, L type, alpha 1C subunit (CACNA1C), diacylglycerol kinase eta (DGKH), gene locus on chromosome 16p12, and polybromo-1 (PBRM1) and very recently neurocan gene (NCAN). Possible common genes underlying psychosis include ZNF804A, CACNA1C, NRGN and PBRM1. The CNV studies suggest that whilst CNVs are found in both SZ and BPD, the large deletions and duplications are more likely found in SZ rather than BPD. The validation of any genetic signal is likely confounded by genetic and phenotypic heterogeneities which are influenced by epistatic, epigenetic and gene-environment interactions. There is a pressing need to better integrate the multiple research platforms including systems biology computational models, genomics, cross disorder phenotyping studies, transcriptomics, proteomics, metabolomics, neuroimaging and clinical correlations in order to get us closer to a more enlightened understanding of the genetic and biological basis underlying these potentially crippling conditions.

White matter abnormalities in major depression: evidence from post-mortem, neuroimaging and genetic studies.

BACKGROUND: Until more recently, most studies have examined the changes in brain gray matter in major depressive disorder (MDD) with less studies focusing on understanding white matter pathology in MDD. Studies of brain white matter volume changes, connectivity disruptions, as well as genetic factors affecting myelination can throw light on the nature of white matter abnormalities underpinning MDD. METHODS: We review the state of the art understanding of white matter changes in MDD from the extant neuropathology, neuroimaging and neurogenetic studies. RESULTS: Overall, data are sparse and mostly conducted in older patients with MDD. Post-mortem studies have highlighted pathology of white matter in prefrontal brain region in terms of decreased oligodendrocyte density, reductions in the expression of genes related to oligodendrocyte function, molecular changes in intercellular cell adhesion molecule (ICAM) expression levels and suggestion of possible mechanism of ischemia. Structural magnetic resonance imaging studies have revealed deep white matter hyperintensities which are associated with clinical severity, and treatment responsiveness. LIMITATIONS: There is a particular dearth of genetic studies related to white matter pathology, studies of younger depressed subjects and specifically probing cortical and subcortical white matter pathology together in MDD. CONCLUSIONS: Future investigations would want to study white matter changes in different cerebral regions and incorporate multimodal and longitudinal levels of examination in order to better grasp the neural basis of this condition.

Cortical and subcortical white matter abnormalities in adults with remitted first-episode mania revealed by Tract-Based Spatial Statistics.

OBJECTIVES: Abnormalities of brain white matter have been noted in structural magnetic resonance imaging and diffusion tensor imaging (DTI) studies of bipolar disorder, but there are fewer investigations specifically examining white matter integrity early in the course of illness. In this study, we employed DTI to elucidate white matter changes in adult patients with remitted first-episode mania and hypothesized that first-episode mania was associated with decreased fractional anisotropy in cortical (frontal) and subcortical (thalamus, striatum) white matter as well as white matter tracts (cingulum, corpus callosum). METHODS: Diffusion tensor images were acquired from 16 patients with remitted first-episode mania and 16 healthy controls matched for age, gender, handedness, and years of education. Fractional anisotropy and radial and axial diffusivities were analyzed using Tract-Based Spatial Statistics. RESULTS: Patients had lower fractional anisotropy and higher radial diffusivity in the left anterior frontal white matter, right posterior thalamic radiation, left cingulum, and bilateral sagittal striatum. In addition, increased radial diffusivity was found in the left corpus callosum. CONCLUSION: Our findings highlighted that white matter abnormalities were present by the time of remission of first-episode mania. The widespread occurrence of these white matter abnormalities both in first-episode mania and chronic bipolar disorder suggested that disruption of white matter cortical-subcortical networks as well as projection, associative, and commissural tracts is a hallmark of the illness.

Hippocampal-cortical structural connectivity disruptions in schizophrenia: an integrated perspective from hippocampal shape, cortical thickness, and integrity of white matter bundles.

Disruptions in the hippocampal-cortical functional connectivities have been implicated in schizophrenia but less is known about their anatomical disconnectivities and association with clinical symptoms. We assessed the anatomical relationships between hippocampal shape, cortical thickness, and integrity of white matter bundles interconnecting them in this study. A brain mapping technique, large deformation diffeomorphic metric mapping, was used to analyze structural magnetic resonance imaging and diffusion tensor imaging scans of 126 schizophrenia patients and 77 matched healthy controls. We found that schizophrenia patients had surface inward-deformation in bilateral anterior hippocampi and cortical thinning in the regions of bilateral prefrontal, temporal, and occipital cortices compared with healthy controls. Anterior hippocampal shape deformity was associated with cortical thinning in the brain regions involved in visuo-spatial and verbal memory pathways. Canonical analysis revealed that greater disruptions in the hippocampal-cortical connectivity were associated with more severe negative symptoms in schizophrenia. Furthermore, fractional anisotropy in the fornix and cingulum bundles were reduced indicating abnormal integration of white matter between hippocampus and cortex in schizophrenia. Our findings suggested that aberrant structural hippocampal-cortical connectivities may serve as a marker of the illness and provide further structural evidence to support the notion of schizophrenia as a disorder of brain connectivity.

The Schizophrenia Cognition Rating Scale: validation of an interview-based assessment of cognitive functioning in Asian patients with schizophrenia.

Growing interest in cognitive deficits associated with schizophrenia has led to the need for a clinician-friendly cognitive instrument. The Schizophrenia Cognition Rating Scale (SCoRS), recognized for its brevity and ease of administration, has proven to be a valid and reliable measure of overall cognition in schizophrenia patients. However, there has been no such validation in an Asian context. This SCoRS validation study involved 103 patient and 48 control subjects within an Asian population. Test-retest reliability, sensitivity of the instrument to cognitive differences between patients with schizophrenia and healthy controls as well as validity by comparing with a standardised performance-based cognitive battery, the Brief Assessment of Cognition in Schizophrenia (BACS) were assessed. Our findings indicated that SCoRS is highly reliable (ICC=0.984) and sensitive to cognitive dysfunction. SCoRS is significantly correlated with BACS composite scores and predicted functional outcomes as measured by Global Assessment of Functioning (GAF) and World Health Organisation-Quality of Life (WHO QOL) within an Asian population. SCoRS represents a clinician-friendly cognitive assessment tool that incorporates third-party feedback and might be employed in clinical practice to better evaluate and manage schizophrenia.

Genetic association studies of glutamate, GABA and related genes in schizophrenia and bipolar disorder: a decade of advance.

Schizophrenia (SZ) and bipolar disorder (BD) are debilitating neurobehavioural disorders likely influenced by genetic and non-genetic factors and which can be seen as complex disorders of synaptic neurotransmission. The glutamatergic and GABAergic neurotransmission systems have been implicated in both diseases and we have reviewed extensive literature over a decade for evidence to support the association of glutamate and GABA genes in SZ and BD. Candidate-gene based population and family association studies have implicated some ionotrophic glutamate receptor genes (GRIN1, GRIN2A, GRIN2B and GRIK3), metabotropic glutamate receptor genes (such as GRM3), the G72/G30 locus and GABAergic genes (e.g. GAD1 and GABRB2) in both illnesses to varying degrees, but further replication studies are needed to validate these results. There is at present no consensus on specific single nucleotide polymorphisms or haplotypes associated with the particular candidate gene loci in these illnesses. The genetic architecture of glutamate systems in bipolar disorder need to be better studied in view of recent data suggesting an overlap in the genetic aetiology of SZ and BD. There is a pressing need to integrate research platforms in genomics, epistatic models, proteomics, metabolomics, neuroimaging technology and translational studies in order to allow a more integrated understanding of glutamate and GABAergic signalling processes and aberrations in SZ and BD as well as their relationships with clinical presentations and treatment progress over time.

Neurocognitive, clinical and functional correlates of subjective quality of life in Asian outpatients with schizophrenia.

Quality of life (QOL) impairment is evident in patients with schizophrenia and is increasingly recognised as an important evaluation criterion of treatment outcome. Hence, this study aimed to identify the neurocognitive, clinical and functional parameters associated with subjective QOL in patients with schizophrenia within an Asian context, and specifically in an outpatient setting. This study was conducted on 83 outpatients with DSM-IV diagnosis of schizophrenia, and 47 age- and gender-matched healthy controls. All participants were administered with the World Health Organisation Quality of Life Assessment-Brief Form (WHOQOL-BREF) and Brief Assessment of Cognition in Schizophrenia (BACS), to measure quality of life and cognitive function respectively. Patients were also assessed for severity of psychopathology, as well as level of psychosocial functioning, using the Positive and Negative Syndrome Scale (PANSS) and Global Assessment of Functioning (GAF) rating scales respectively. Specific psychopathology (greater severity of PANSS negative symptoms, general psychopathology subscale scores), cognitive deficits (working and verbal memories), and lower GAF scores were correlated with poorer QOL in patients. Multivariate analyses revealed that younger age, being single and lower level of psychosocial functioning were associated with poorer QOL but level of psychosocial functioning did not appear to mediate the effects of symptoms and neurocognitive deficits on QOL. Overall, this study highlighted the need for clinicians to pay more attention to these clinical, neurocognitive and functional parameters and their integrative relationships with QOL in order to optimise the treatment outcomes of patients with schizophrenia.

Duration of illness, regional brain morphology and neurocognitive correlates in schizophrenia.

INTRODUCTION: Previous studies examining brain effects of duration of illness in schizophrenia have focused on either cortical or subcortical structures. Hence this study sought to elucidate the regional grey matter changes (both cortical and subcortical) and neurocognitive correlates with increased duration of illness in a large sample of patients with schizophrenia using voxel-based morphometry. MATERIALS AND METHODS: Ninety patients (72 males and 18 females) with DSM-IV diagnosis of schizophrenia were recruited and assessed using magnetic resonance imaging and a battery of neuropsychological tests. RESULTS: A longer duration of illness was associated with smaller grey matter volumes in the left superior frontal gyrus, bilateral putamen, right superior temporal gyrus, right superior occipital gyrus as well as the right thalamus. No region showed increased grey matter volume above threshold with longer duration of illness. Longer duration of illness was correlated with poorer attention. CONCLUSIONS: The grey matter reductions in different brain regions highlighted that a distributed network of cortical and subcortical regions was associated with duration of illness. This is consistent with neural models that implicate involvement of thalamo-cortical circuitry as the disruption in these neural pathways can result in specific deficits such as poorer attention. The results have implications for the understanding of brain changes in schizophrenia, and with further studies, may guide better tailored and targeted clinical management in terms of reducing the impact of duration of illness on neural substrates in schizophrenia in the future.