Quantitative neural indicators of liability to schizophrenia: implications for molecular genetic studies

While schizophrenia is substantially heritable, the disorder's molecular genetic basis remains elusive. These efforts have been hindered by an inability to detect nonclinically-penetrant carriers of the predisposing genes and by uncertainties concerning the nature of the non-genetic influences and the extent of locus heterogeneity. The "endophenotype" approach is an alternative method for measuring phenotypic variation that may facilitate the identification of susceptibility genes in the context of complexly-inherited traits. Here we describe the application of this method to measures of brain structure and function in samples of schizophrenia patients and their non-ill first-degree relatives (siblings and co-twins). Our results suggest that there are likely to be multiple heritable dimensions of the central nervous system pathology in schizophrenia, each under the influence of a partially distinct set of genes, one of which involves disturbances in the structure and functioning of frontal lobe systems involved in working memory and another of which appears to render the brain more susceptible to damage to subcortical systems involved in long-term memory following oxygen deprivation in utero. Measures sensitive to quantitative variation in these dimensions of the central nervous system compromise should allow non-penetrant gene carriers to become informative for genetic linkage and facilitate detection of different genetic loci contributing to discrete aspects of disease liability.