Schizophrenia and the question of genetic heterogeneity

Despite major advances in psychiatric diagnosis during the past 20 years, boundaries of the schizophrenic syndrome remain elusive. Moreover, in pedigrees containing cases of schizophrenia there are marked between-pedigree differences with respect to prognosis, familial patterns of psychiatric illness, drug response, and especially association of affected status with a specific chromosomal locus. Such between-pedigree differences suggest the syndrome may be made up of several different diseases. Link age of affected status to specific loci may aid in resolving genetic heterogeneity. Large multigenerational informative pedigrees may permit the separation into those that do and do not link to a genomic locus of interest. Admixture analysis of smaller informative pedigrees may permit separation of linked and unlinked pedigrees on the basis of differences in the recombination fraction. Finally, biological "markers" can be used before the genetic analysis to separate putative linked and unlinked pedigrees. The combined study of genetic linkage and clinical heterogeneity will aid in the resolution of etiological heterogeneity of schizophrenia and the delineation of meaningful diagnostic boundaries.