Turning point in the design of linkage studies of schizophrenia

C. R. Cloninger

    Research output: Contribution to journalArticle

    106 Scopus citations

    Abstract

    Despite extensive genomic scans, linkage studies of multiplex pedigrees have been unable to produce replicable evidence of genes predisposing to schizophrenia. This indicates that it is unlikely that a single gene accounts for a majority of cases of schizophrenia, even in multiplex pedigrees. It is most likely that schizophrenia is caused by the nonlinear interaction of multiple genetic and environmental factors influencing brain development and function. This conclusion has strong implications for the design of linkage and association studies. Recently designed linkage studies involve several improvements to deal with extensive locus heterogeneity and multiplicative interaction. These improvements include much larger samples of pedigrees, systematic ascertainment and sequential extension rules, and standardized procedures at multiple sites to facilitate collaboration and replication. Future improvements are likely to require advances in the assessment of clinical and neurobiological variability in multiplex pedigrees, more systematic environmental assessment, and advances in analytic methods to deal with multiplicative interaction. Rather than focusing only on schizophrenia as one or more discrete disorders, future linkage efforts should also consider the etiology of individual clinical syndromes or dimensional components of risk that interact to cause the complex pattern of syndromal comorbidity observed within schizophrenics and their families.

    Original languageEnglish
    Pages (from-to)83-92
    Number of pages10
    JournalAmerican journal of medical genetics
    Volume54
    Issue number2
    DOIs
    StatePublished - Jun 8 1994

    Keywords

    • comorbidity
    • epistasis
    • gene-environment interaction
    • genetic linkage analysis
    • genetic models
    • heterogeneity
    • schizophrenia

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