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  • Original Research Article
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Linkage analysis of candidate regions using a composite neurocognitive phenotype correlated with schizophrenia

Molecular Psychiatry volume 8, pages 511–523 (2003)Cite this article

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.

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Acknowledgements

This work was supported by the National Health and Medical Research Council (NHMRC), Australia (grants 960579, 990701 and 129060) and the Graylands Hospital (Perth, Western Australia, Australia). The following individuals made specific contributions to study design, data collection, data analysis, and manuscript editing. Perth: J Box, JE Cooper, B Jansen, J Johnston, R Kaiser, V Morgan, R Stienstra, J Todd, D Vile, D Wood, and P Wynn Owen; Duke University, Durham, NC, USA: E Corder, J Wagner, K Manton. The cooperation of the clinical and administrative staff at Graylands Hospital, Perth, is gratefully acknowledged. We especially thank the patients, family members, and other volunteers who participated in this study.

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Authors and Affiliations

  1. School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia

    J F Hallmayer, A Jablensky & P Michie

  2. Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, Perth, Australia

    J F Hallmayer, A Jablensky, P Michie, B Salmon, H Wichmann, D Rock, M D'Ercole, S Howell, M Dragović & A Kent

  3. Western Australian Institute of Medical Research, Perth, Australia

    A Jablensky

  4. Center for Demographic Studies, Duke University, Durham, NC, USA

    M Woodbury

  5. Community Mental Health Centre, Osborne Park, Perth, Australia

    J Combrinck

  6. School of Psychology, University of Western Australia, Perth, Australia

    P Michie

  7. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    J F Hallmayer

  8. School of Behavioural Sciences, University of Newcastle, Newcastle, Australia

    P Michie

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Hallmayer, J., Jablensky, A., Michie, P. et al. Linkage analysis of candidate regions using a composite neurocognitive phenotype correlated with schizophrenia. Mol Psychiatry 8, 511–523 (2003). https://doi.org/10.1038/sj.mp.4001273

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