Schizophrenia unquestionably has a significant genetic component but the nature of that genetic component remains unresolved. Genetic linkage is a powerful research paradigm for identifying major loci that might exist as causes of some cases of schizophrenia. Two major problems have complicated previous genetic linkage studies of schizophrenia: The inability to infer precisely the inheritance pattern of the putative major segregating in high density families and the difficulty in inferring precisely the segregation of marker loci in sparse, complex, and disjointed pedigrees. We propose genetic linkage studies that will address both of those issues. The improved inference of the major locus will be possible because of the use of additional diagnostic as well as psychophysiological evaluations of all family members. This approach, motivated by a latent trait model, is already underway as part of a funded research project. This present application is to fund a more exhaustive and detailed evaluation of how genetic material has in fact been transmitted within these large high density families using new technologies to evaluate, in an efficient and accurate way, the class of DNA polymorphisms known as short tandem repeats. These polymorphisms are present every 10 or so kilobases throughout the genome, have heterozygosities generally greater than 70%, and have discrete allelic states easy to classify with semi-automated methodologies.
