Copy Number Variations in DISC1 and DISC1-Interacting Partners in Major Mental Illness.

Robust statistical, genetic and functional evidence supports a role for DISC1 in the aetiology of major mental illness. Furthermore, many of its protein-binding partners show evidence for involvement in the pathophysiology of a range of neurodevelopmental and psychiatric disorders. Copy number variants (CNVs) are suspected to play an important causal role in these disorders. In this study, CNV analysis of DISC1 and its binding partners PAFAH1B1, NDE1, NDEL1, FEZ1, MAP1A, CIT and PDE4B in Scottish and Northern Swedish population-based samples was carried out using multiplex amplicon quantification. Here, we report the finding of rare CNVs in DISC1, NDE1 (together with adjacent genes within the 16p13.11 duplication), NDEL1 (including the overlapping MYH10 gene) and CIT. Our findings provide further evidence for involvement of DISC1 and its interaction partners in neuropsychiatric disorders and also for a role of structural variants in the aetiology of these devastating diseases.

Smooth pursuit and visual scanpaths: Independence of two candidate oculomotor risk markers for schizophrenia.

OBJECTIVES: Smooth pursuit and visual scanpath deficits are candidate trait markers for schizophrenia. It is not clear whether eye tracking dysfunction (ETD) and atypical scanpath behaviour are the product of the same underlying neurobiological processes. We have examined co-occurrence of ETD and scanpath disturbance in individuals with schizophrenia and healthy volunteers. METHODS: Eye movements of individuals with schizophrenia (N = 96) and non-clinical age-matched comparison participants (N = 100) were recorded using non-invasive infrared oculography during smooth pursuit in both predictable (horizontal sinusoid) and less predictable (Lissajous sinusoid) conditions and a free viewing scanpath task. RESULTS: Individuals with schizophrenia demonstrated scanning deficits in both tasks. There was no association between performance measures of smooth pursuit and scene scanpaths in patient or control groups. Odds ratios comparing the likelihood of scanpath dysfunction when ETD was present, and the likelihood of finding scanpath dysfunction when ETD was absent were not significant in patients or controls in either pursuit variant, suggesting that ETD and scanpath dysfunction are independent anomalies in schizophrenia. CONCLUSION: ETD and scanpath disturbance appear to reflect independent oculomotor or neurocognitive deficits in schizophrenia. Each task may confer unique information about the pathophysiology of psychosis.

Atypical scanpaths in schizophrenia: evidence of a trait- or state-dependent phenomenon?

The development of trait markers of schizophrenia would represent an important advance in understanding the genetic architecture of the disease. To date, no candidate markers have satisfied all of the trait marker criteria, and many are not specific to the schizophrenia spectrum. Abnormalities in visual scanpaths are frequently reported in patients with schizophrenia and are emerging as a novel candidate for a schizophrenia biomarker. Here we review the suitability of scanpath measures as a target for trait marker research in schizophrenia. Papers reporting scanpath patterns in patients with schizophrenia were identified by PubMed and Google Scholar searches and by scanning reference lists in relevant articles. Search terms included "schizophrenia," "psychosis," "scanpath," "scan path," "fixation," "saccade" and "eye movement." Scanpath abnormalities afford impressive sensitivity and specificity and appear largely independent of psychotropic medications. Scanpaths may demonstrate some fluctuation with symptomatology and may be useful in illuminating illness state or subtypes. However, there is evidence that viewing behaviours remain atypical regardless of symptom remission and may be present in unaffected relatives of individuals with schizophrenia. This research is in its early stages, and further investigation regarding patterns of inheritance is required. Our findings support scanpath measures as a favourable topic for further investigation as a trait marker.

Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia.

CONTEXT: Recent studies suggest that copy number variation in the human genome is extensive and may play an important role in susceptibility to disease, including neuropsychiatric disorders such as schizophrenia and autism. The possible involvement of copy number variants (CNVs) in bipolar disorder has received little attention to date. OBJECTIVES: To determine whether large (>100,000 base pairs) and rare (found in <1% of the population) CNVs are associated with susceptibility to bipolar disorder and to compare with findings in schizophrenia. DESIGN: A genome-wide survey of large, rare CNVs in a case-control sample using a high-density microarray. SETTING: The Wellcome Trust Case Control Consortium. PARTICIPANTS: There were 1697 cases of bipolar disorder and 2806 nonpsychiatric controls. All participants were white UK residents. MAIN OUTCOME MEASURES: Overall load of CNVs and presence of rare CNVs. RESULTS: The burden of CNVs in bipolar disorder was not increased compared with controls and was significantly less than in schizophrenia cases. The CNVs previously implicated in the etiology of schizophrenia were not more common in cases with bipolar disorder. CONCLUSIONS: Schizophrenia and bipolar disorder differ with respect to CNV burden in general and association with specific CNVs in particular. Our data are consistent with the possibility that possession of large, rare deletions may modify the phenotype in those at risk of psychosis: those possessing such events are more likely to be diagnosed as having schizophrenia, and those without them are more likely to be diagnosed as having bipolar disorder.

Visual scan paths in first-episode schizophrenia and cannabis-induced psychosis.

OBJECTIVE: Patterns of successive saccades and fixations (scan paths) that are made while viewing images are often spatially restricted in schizophrenia, but the relation with cannabis-induced psychosis has not been examined. We used higher-order statistical methods to examine spatiotemporal characteristics of scan paths to determine whether viewing behaviour was distinguishable on a continuum. METHODS: Patients with early acute first-episode paranoid schizophrenia (SCH; n = 11), cannabis-induced psychosis (CIP; n = 6) and unaffected control subjects (n = 22) undertook a task requiring free viewing of facial, fractal and landscape images for 5 seconds while their eye movements were recorded. Frequencies and distributions of saccades and fixations were calculated in relation to image regions examined during each trial. RESULTS: Findings were independent of image category, indicating generalized scanning deficits. Compared with control subjects, patients with SCH and CIP made fewer saccades and fewer fixations of longer duration. In turn, the spatial distribution of fixations in CIP patients was more clustered than in SCH and control subjects. The diversity of features fixated in subjects with CIP was also lower than in SCH patients and control subjects. CONCLUSION: A continuous approach to characterizing scan path changes in different phenotypes suggests that CIP shares some of the abnormalities of SCH but can be distinguished with measures that are sensitive to cognitive strategies active or inhibited during visual exploration.