The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder

Genome-wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium-channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the zinc-finger ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract-based spatial statistics and threshold-free cluster enhancement significance correction (p < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebelleum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ-specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737

Nonlinear complexity analysis of brain fMRI signals in schizophrenia

Peer reviewedPublisher PD

Gender Differences in White Matter Microstructure

Sexual dimorphism in human brain structure is well recognised, but little is known about gender differences in white matter microstructure. We used diffusion tensor imaging to explore differences in fractional anisotropy (FA), an index of microstructural integrity.A whole brain analysis of 135 matched subjects (90 men and 45 women) using a 1.5 T scanner. A region of interest (ROI) analysis was used to confirm those results where proximity to CSF raised the possibility of partial-volume artefact.Men had higher fractional anisotropy (FA) in cerebellar white matter and in the left superior longitudinal fasciculus; women had higher FA in the corpus callosum, confirmed by ROI.The size of the differences was substantial--of the same order as that attributed to some pathology--suggesting gender may be a potentially significant confound in unbalanced clinical studies. There are several previous reports of difference in the corpus callosum, though they disagree on the direction of difference; our findings in the cerebellum and the superior longitudinal fasciculus have not previously been noted. The higher FA in women may reflect greater efficiency of a smaller corpus callosum. The relatively increased superior longitudinal fasciculus and cerebellar FA in men may reflect their increased language lateralisation and enhanced motor development, respectively

The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project

BACKGROUND: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. METHODS: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. RESULTS: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia

White Matter Microstructural Organization Is Higher with Age in Adult Superior Cerebellar Peduncles

Using diffusion tensor imaging, we conducted an exploratory investigation of the relationship between white matter tract microstructure and age in 200 healthy adult subjects using tract-based spatial statistics (TBSS). Though most tracts showed the slight decline in microstructural organization with age widely noted, in both superior cerebellar peduncles (SCP) it correlated positively with age, a result not previously reported. We confirmed this by using an alternative method, and by repeating our TBSS analysis in an additional sample of 133 healthy adults. In exploring this surprising result we considered the possibility that this might arise from the continual cognitive and motor refinement that is enacted in the cerebellum: we found that tract microstructure in both SCPs was also strongly correlated with IQ, again in contrast with all other tracts, and its relationship with age mediated by IQ, as a training model would predict

Modelling Genetic and Environmental Influences on Brain Volume in Twins with Schizophrenia

This journal suppl. entitled: Abstracts of the 4th Biennial Schizophrenia International Research ConferencePoster presentationConference theme: Fostering Collaboration in Schizophrenia ResearchBACKGROUND: Whole brain and grey matter volumes are reduced in schizophrenia. How these pathological abnormalities are influenced by schizophrenia’s genetic and environmental risk remains less clear. METHODS: We investigated the relationship between genetic, common and unique environmental risk on brain volumes in monozygotic and dizygotic twin pairs varying in their concordance for schizophrenia, and healthy control twins. Total brain, grey and white matter volumes were established from structural magnetic resonance images using an automated alogorithm in SPM8 from 86 twin pairs (n=168). Hippocampal volumes were measured manually in the same sample. Between group differences in brain volumes were tested before full genetic modelling in Mx. RESULTS: We found that whole brain, grey, white and right hippocampal volumes were smaller in probands with schizophrenia compared to healthy controls. Well co-twins from DZ discordant pairs also had smaller hippocampal volumes compared to the healthy controls. Whole brain, grey and white matter volumes were heritable, while hippocampal volume was subject to significant common environmental effects. All of the brain volumes tested had a significant negative phenotypic correlation with schizophrenia. Lower birth weight and hypoxia were both associated with lower whole brain volumes, and with lower white and grey matter volumes respectively. There were no significant effects in the patients of cumulative antipsychotic exposure. DISCUSSION: Our data suggest that total brain, grey, white matter and hippocampal volume reductions are associated with schizophrenia. Whole brain and white matter volumes were most strongly linked to genetic effects. Hippocampal volume reductions appear to be particularly sensitive to environmental effects

Schizophrenia moderates the relationship between white matter integrity and cognition

Cognitive impairment is a primary feature of schizophrenia, with alterations in several cognitive domains appearing in the pre-morbid phase of the disorder. White matter microstructure is also affected in schizophrenia and considered to be related to cognition, but the relationship of the two is unclear. As interaction between cognition and white matter structure involves the interplay of several brain structures and cognitive abilities, investigative methods which can examine the interaction of multiple variables are preferred. A multiple-groups structural equation model (SEM) was used to assess the relationship between diffusion tension imaging data (fractional anisotropy of selected white matter tracts) and cognitive abilities of 196 subjects - 135 healthy subjects and 61 patients with schizophrenia. It was found that multiple-indicators, multiple-causes model best fitted the data analysed. Schizophrenia moderated the relation of white matter function on cognition with a large effect size. This paper extends previous work on modelling intelligence within a SEM framework by incorporating neurological elements into the model, and shows that white matter microstructure in patients with schizophrenia interacts with cognitive abilities

Genetic and Environmental Influences on Brain Function In Schizophrenia. An FMRI Study of the Maudsley Twin and Family Cohorts

Oral presentation: Advances in Imaging in Schizophrenia IConference theme: Fostering Collaboration in Schizophrenia ResearchThis journal suppl. entitled: Abstracts of the 4th Biennial Schizophrenia International Research ConferenceBACKGROUND: Schizophrenia is a heritable but aetiologically complex disorder. Intermediate phenotypes as quantitative traits pathophysiologically closer to the underlying genetic risks represent an experimental strategy to help address this complexity. Verbal fluency performance satisfies many criteria for an intermediate phenotype for schizophrenia. Our aim was to assess the influence of genetic and environmental factors on this executive function task in schizophrenia. METHODS: We used a twin-sibling study of 206 subjects; 163 twins, varying in their zygosity and concordance for schizophrenia, and 43 singletons from siblings varying in their concordance for schizophrenia. We assessed performance and regional brain activation using functional magnetic resonance imaging, during a phonological verbal fluency task. After between group testing, we conducted full genetic modelling. RESULTS: Across groups there was a differential pattern of activation in fronto-temporal areas. Patients and their unaffected relatives developed greater activation in the left inferior frontal gyrus, and greater deactivation in the left hippocampal and middle temporal gyri bilaterally. These features were maximally evident in subjects with schizophrenia, and least in controls. When the analysis was restricted to the unaffected relatives and healthy controls, a similar pattern was evident, with the unaffected relatives showing greater inferior frontal and left superior temporal activation, and greater right parahippocampal and right superior/middle temporal deactivation than healthy controls. Genetic modelling indicated a phenotypic correlation between schizophrenia and increased activity in the inferior frontal gyrus and reduced activity in the left middle temporal gyrus and left hippocampus, which was principally due to shared genetic effects. DISCUSSION: Both schizophrenia and its familial vulnerability were associated altered frontal, parahippocampal and temporal activation during verbal fluency. The altered left inferior frontal activity was particularly associated with schizophrenia, while altered right middle/superior temporal and right medial temporal activity were more heritable and more intimately linked to the genetic risk for schizophrenia