Marco Picchioni

Common variants conferring risk of schizophrenia

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ‘genomic disorders’, have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Disruption of the neurexin 1 gene is associated with schizophrenia

Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.

Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder

Studies of the major psychoses, schizophrenia (SZ) and bipolar disorder (BD), have traditionally focused on genetic and environmental risk factors, although more recent work has highlighted an additional role for epigenetic processes in mediating susceptibility. Since monozygotic (MZ) twins share a common DNA sequence, their study represents an ideal design for investigating the contribution of epigenetic factors to disease etiology. We performed a genome-wide analysis of DNA methylation on peripheral blood DNA samples obtained from a unique sample of MZ twin pairs discordant for major psychosis. Numerous loci demonstrated disease-associated DNA methylation differences between twins discordant for SZ and BD individually, and together as a combined major psychosis group. Pathway analysis of our top loci highlighted a significant enrichment of epigenetic changes in biological networks and pathways directly relevant to psychiatric disorder and neurodevelopment. The top psychosis-associated, differentially methylated region, significantly hypomethylated in affected twins, was located in the promoter of ST6GALNAC1 overlapping a previously reported rare genomic duplication observed in SZ. The mean DNA methylation difference at this locus was 6%, but there was considerable heterogeneity between families, with some twin pairs showing a 20% difference in methylation. We subsequently assessed this region in an independent sample of postmortem brain tissue from affected individuals and controls, finding marked hypomethylation (>25%) in a subset of psychosis patients. Overall, our data provide further evidence to support a role for DNA methylation differences in mediating phenotypic differences between MZ twins and in the etiology of both SZ and BD.

Altered connections on the road to psychopathy

Psychopathy is strongly associated with serious criminal behaviour (for example, rape and murder) and recidivism. However, the biological basis of psychopathy remains poorly understood. Earlier studies suggested that dysfunction of the amygdala and/or orbitofrontal cortex (OFC) may underpin psychopathy. Nobody, however, has ever studied the white matter connections (such as the uncinate fasciculus (UF)) linking these structures in psychopaths. Therefore, we used in vivo diffusion tensor magnetic resonance imaging (DT-MRI) tractography to analyse the microstructural integrity of the UF in psychopaths (defined by a Psychopathy Checklist Revised (PCL-R) score of ⩾25) with convictions that included attempted murder, manslaughter, multiple rape with strangulation and false imprisonment. We report significantly reduced fractional anisotropy (FA) (P<0.003), an indirect measure of microstructural integrity, in the UF of psychopaths compared with age- and IQ-matched controls. We also found, within psychopaths, a correlation between measures of antisocial behaviour and anatomical differences in the UF. To confirm that these findings were specific to the limbic amygdala–OFC network, we also studied two ‘non-limbic’ control tracts connecting the posterior visual and auditory areas to the amygdala and the OFC, and found no significant between-group differences. Lastly, to determine that our findings in UF could not be totally explained by non-specific confounds, we carried out a post hoc comparison with a psychiatric control group with a past history of drug abuse and institutionalization. Our findings remained significant. Taken together, these results suggest that abnormalities in a specific amygdala–OFC limbic network underpin the neurobiological basis of psychopathy.

Substantial genetic overlap between neurocognition and schizophrenia: genetic modeling in twin samples

CONTEXT The use of endophenotypes, biological traits that increase the liability to a disorder, represents one strategy to facilitate the detection of susceptibility genes for complex behavioral disorders such as schizophrenia. Establishing that a candidate trait is both heritable and linked genetically to schizophrenia is integral to its validity as an endophenotypic marker. Neurocognitive deficits are among the most promising indicators of increased risk for schizophrenia; however, it is not clear to what extent these deficits are genetically linked to the disorder. OBJECTIVES To quantify the genetic and environmental contributions to the variability of selected neurocognitive measures and to estimate the genetic relationship between these and schizophrenia. DESIGN Genetic model fitting to monozygotic and dizygotic twin data. SETTING United Kingdom psychiatric research institute. PARTICIPANTS Two hundred sixty-seven monozygotic and dizygotic twins concordant and discordant for schizophrenia, and healthy monozygotic and dizygotic control twin pairs. MAIN OUTCOME MEASURES The heritabilities of intelligence, working memory, processing speed, perceptual organization, and verbal comprehension were estimated, and the genetic relationship between each of these and schizophrenia was quantified. RESULTS Genetic influences contributed substantially to all of the cognitive domains, but intelligence and working memory were the most heritable. A significant correlation was found between intelligence and schizophrenia (r = -0.61; 95% confidence interval, -0.71 to -0.48), with shared genetic variance accounting for 92% of the covariance between the two. Genetic influences also explained most of the covariance between working memory and schizophrenia. Significant but lesser portions of covariance between the other cognitive domains and schizophrenia were also found to be genetically shared. Environmental effects, although separately linked to neurocognition and schizophrenia, did not generally contribute to their covariance. CONCLUSION Genomewide searches using factorial designs stratifying for levels of intelligence and working memory will assist in the search for finding quantitative trait loci for schizophrenia.

Acoustic Noise and Functional Magnetic Resonance Imaging: Current Strategies and Future Prospects

Functional magnetic resonance imaging (fMRI) has become the method of choice for studying the neural correlates of cognitive tasks. Nevertheless, the scanner produces acoustic noise during the image acquisition process, which is a problem in the study of auditory pathway and language generally. The scanner acoustic noise not only produces activation in brain regions involved in auditory processing, but also interferes with the stimulus presentation. Several strategies can be used to address this problem, including modifications of hardware and software. Although reduction of the source of the acoustic noise would be ideal, substantial hardware modifications to the current base of installed MRI systems would be required. Therefore, the most common strategy employed to minimize the problem involves software modifications. In this work we consider three main types of acquisitions: compressed, partially silent, and silent. For each implementation, paradigms using block and event‐related designs are assessed. We also provide new data, using a silent event‐related (SER) design, which demonstrate higher blood oxygen level‐dependent (BOLD) response to a simple auditory cue when compared to a conventional image acquisition. J. Magn. Reson. Imaging 2002;16:497–510.

Functional integration between the posterior hippocampus and prefrontal cortex is impaired in both first episode schizophrenia and the at risk mental state

Recent neuroimaging studies have reported deficits in functional integration between prefrontal cortex and the hippocampal formation in schizophrenia. It is unclear whether these alterations are a consequence of chronic illness or its treatment, and whether they are also evident in non-psychotic subjects at increased risk of the disorder. We addressed these issues by investigating prefrontal-hippocampal interactions in patients with first episode schizophrenia and subjects with an At Risk Mental State (ARMS). Using functional Magnetic Resonance Imaging, we measured brain responses from 16 individuals with an ARMS, 10 patients with first episode schizophrenia and 14 healthy controls during a delayed matching to sample task. Dynamic causal modelling was used to estimate the effective connectivity between prefrontal cortex and anterior and posterior hippocampal regions. The normal pattern of effective connectivity from the right posterior hippocampus to the right inferior frontal gyrus was significantly decreased in both first episode patients and subjects with an ARMS (ANOVA; F = 8.16, P = 0.01). Interactions between the inferior frontal gyrus and the anterior part of the hippocampus did not differ across the three groups. Perturbed hippocampal-prefrontal interactions are evident in individuals at high risk of developing psychosis and in patients who have just developed schizophrenia. This suggests that it may be a correlate of increased vulnerability to psychosis and that it is not attributable to an effect of chronic illness or its treatment.

Pattern of neural responses to verbal fluency shows diagnostic specificity for schizophrenia and bipolar disorder

BackgroundImpairments in executive function and language processing are characteristic of both schizophrenia and bipolar disorder. Their functional neuroanatomy demonstrate features that are shared as well as specific to each disorder. Determining the distinct pattern of neural responses in schizophrenia and bipolar disorder may provide biomarkers for their diagnoses.Methods104 participants underwent functional magnetic resonance imaging (fMRI) scans while performing a phonological verbal fluency task. Subjects were 32 patients with schizophrenia in remission, 32 patients with bipolar disorder in an euthymic state, and 40 healthy volunteers. Neural responses to verbal fluency were examined in each group, and the diagnostic potential of the pattern of the neural responses was assessed with machine learning analysis.ResultsDuring the verbal fluency task, both patient groups showed increased activation in the anterior cingulate, left dorsolateral prefrontal cortex and right putamen as compared to healthy controls, as well as reduced deactivation of precuneus and posterior cingulate. The magnitude of activation was greatest in patients with schizophrenia, followed by patients with bipolar disorder and then healthy individuals. Additional recruitment in the right inferior frontal and right dorsolateral prefrontal cortices was observed in schizophrenia relative to both bipolar disorder and healthy subjects. The pattern of neural responses correctly identified individual patients with schizophrenia with an accuracy of 92%, and those with bipolar disorder with an accuracy of 79% in which mis-classification was typically of bipolar subjects as healthy controls.ConclusionsIn summary, both schizophrenia and bipolar disorder are associated with altered function in prefrontal, striatal and default mode networks, but the magnitude of this dysfunction is particularly marked in schizophrenia. The pattern of response to verbal fluency is highly diagnostic for schizophrenia and distinct from bipolar disorder. Pattern classification of functional MRI measurements of language processing is a potential diagnostic marker of schizophrenia.

Brain MRI abnormalities in schizophrenia : same genes or same environment ?

BACKGROUND Structural brain volume abnormalities are among the most extensively studied endophenotypes in schizophrenia. Bivariate genetic model fitting (adjusted to account for selection) was used to quantify the genetic relationship between schizophrenia and brain volumes and to estimate the heritability of these volumes. METHOD We demonstrated by simulation that the adjusted genetic model produced unbiased estimates for endophenotype heritability and the genetic and environmental correlations. The model was applied to brain volumes (whole brain, hippocampus, third and lateral ventricles) in a sample of 14 monozygotic (MZ) twin pairs concordant for schizophrenia, 10 MZ discordant pairs, 17 MZ control pairs, 22 discordant sibling pairs, three concordant sibling pairs, and 114 healthy control subjects. RESULTS Whole brain showed a substantial heritability (88%) and lateral ventricles substantial common environmental effects (67%). Whole brain showed a significant genetic correlation with schizophrenia, whereas lateral ventricles showed a significant individual specific correlation with schizophrenia. There were significant familial effects for hippocampus and third ventricle, but the analyses could not resolve whether these were genetic or environmental in origin (around 30%each). CONCLUSIONS Using genetic model fitting on twin and sibling data we have demonstrated differential sources of covariation between schizophrenia and brain volumes, genetic in the case of whole brain volume and individual specific environment in the case of lateral ventricles.

White matter microstructure in schizophrenia: effects of disorder, duration and medication

Background Diffusion tensor magnetic resonance imaging studies in schizophrenia to date have been largely inconsistent. This may reflect variation in methodology, and the use of small samples with differing illness duration and medication exposure. Aims To determine the extent and location of white matter microstructural changes in schizophrenia, using optimised diffusion tensor imaging in a large patient sample, and to consider the effects of illness duration and medication exposure. Method Scans from 76 patients with schizophrenia and 76 matched controls were used to compare fractional anisotropy, a measure of white matter microstructural integrity, between the groups. Results We found widespread clusters of reduced fractional anisotropy in patients, affecting most major white matter tracts. These reductions did not correlate with illness duration, and there was no difference between age-matched chronically and briefly medicated patients. Conclusions The finding of widespread fractional anisotropy reductions in our larger sample of patients with schizophrenia may explain some of the inconsistent findings of previous, smaller studies.