J Combrinck

Mental Health Council of Australia, Canberra, Australian Capital Territory, Australia

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Publications (2)20.73 Total impact

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    ABSTRACT: As schizophrenia is genetically and clinically heterogeneous, systematic investigations are required to determine whether ICD-10 or DSM-IV categorical diagnoses identify a phenotype suitable and sufficient for genetic research, or whether correlated phenotypes incorporating neurocognitive performance and personality traits provide a phenotypic characterisation that accounts better for the underlying variation. We utilised a grade of membership (GoM) model (a mathematical typology developed for studies of complex biological systems) to integrate multiple cognitive and personality measurements into a limited number of composite graded traits (latent pure types) in a sample of 61 nuclear families comprising 80 subjects with ICD-10/DSM-IV schizophrenia or schizophrenia spectrum disorders and 138 nonpsychotic first-degree relatives. GoM probability scores, computed for all subjects, allowed individuals to be partly assigned to more than one pure type. Two distinct and contrasting neurocognitive phenotypes, one familial, associated with paranoid schizophrenia, and one sporadic, associated with nonparanoid schizophrenia, accounted for 74% of the affected subjects. Combining clinical diagnosis with GoM scores to stratify the entire sample into liability classes, and using variance component analysis (SOLAR), in addition to parametric and nonparametric multipoint linkage analysis, we explored candidate regions on chromosomes 6, 10 and 22. The results indicated suggestive linkage for the familial neurocognitive phenotype (multipoint MLS 2.6 under a low-penetrance model and MLS>3.0 under a high-penetrance model) to a 14 cM area on chromosome 6, including the entire HLA region. Results for chromosomes 10 and 22 were negative. The findings suggest that the familial neurocognitive phenotype may be a pleiotropic expression of genes underlying the susceptibility to paranoid schizophrenia. We conclude that use of composite neurocognitive and personality trait measurements as correlated phenotypes supplementing clinical diagnosis can help stratify the liability to schizophrenia across all members of families prior to linkage, allow the search for susceptibility genes to focus selectively on subsets of families at high genetic risk, and augment considerably the power of genetic analysis.
    Molecular Psychiatry 05/2003; 8(5):511-23. · 15.15 Impact Factor
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    ABSTRACT: Inhibitory deficits have been frequently reported in schizophrenia. Such deficits are usually associated with activities of prefrontal cortex and related networks. An understanding of intentional inhibitory control requires knowledge of how actions are planned and initiated and the components involved in stopping these actions. Patients with schizophrenia, a psychosis comparison group and a healthy control group participated in a visual choice reaction time (go) task and attempted to inhibit their responses to the go task when an auditory 'stop' signal was heard. Schizophrenia patients demonstrated significantly slower response execution but the estimated speed of inhibition was not significantly different from that of healthy controls. Both patient groups were impaired in their ability to inhibit a response across a range of stop-signal delays. The poorer performance of schizophrenia patients only was related to a difficulty in reliably triggering the inhibitory response. Impaired response inhibition is not unique to schizophrenia. However, the nature of their problem is markedly different from that of other psychopathological groups. Possible neural mechanisms underpinning difficulties in triggering inhibitory responses and in the voluntary initiation of actions in schizophrenia are considered.
    Psychological Medicine 03/2002; 32(2):287-97. · 5.59 Impact Factor