Quantitative neural indicators of liability to schizophrenia: Implicationsfor molecular genetic studies

While schizophrenia is substantially heritable, the disorder's molecular ge netic basis remains elusive. These efforts have been hindered by an inabili ty to detect non-clinically-penetrant carriers of the predisposing genes an d by uncertainties concerning the nature of the non-genetic influences and the extent of locus heterogeneity. The "endophenotype" approach is an alter native method for measuring phenotypic variation that may facilitate the id entification of susceptibility genes in the context of complexly-inherited traits. Here we describe the application of this method to measures of brai n structure and function in samples of schizophrenia patients and their non -ill first-degree relatives (siblings and co-twins), Our results suggest th at there are likely to be multiple heritable dimensions of the central nerv ous system pathology in schizophrenia, each under the influence of a partia lly distinct set of genes, one of which involves disturbances in the struct ure 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 deprivati on in utero, Measures sensitive to quantitative variation in these dimensio ns of the central nervous system compromise should allow non-penetrant gene carriers to become informative for genetic linkage and facilitate detectio n of different genetic loci contributing to discrete aspects of disease lia bility. Am. J, Med, Genet, (Neuropsychiatr. Genet,) 105:16-19, 2001, (C) 20 01 Wiley-Liss, Inc.