Results from the study by Sherrington et a]. [1988] indicate that the maximum lod score (3.2) from a linkage analysis between narrowly defined clinical diagnostic criteria for schizophrenia and polymorphic markers on chromosome 5 is lower than that (6.5) from an analogous analysis between broadly defined clinical criteria for psychiatric illness and these same markers. Should these results be interpreted to indicate that in the families studied the narrowly defined clinical phenotype for schizophrenia is due to a single locus located on chromosome 5 , with the inclusion of other psychiatric illness spuriously inflating the lod score? Or do they indicate that a locus located on chromosome 5 is responsible, at least in part, for a spectrum of psychiatric illness that can include schizophrenia? We agree with Risch [ 19901 that current evidence indicates that single-locus segregation can account for at most a small fraction of the cases of schizophrenia in general. We further believe that there is no strong evidence that schizophrenia is largely polygenic, in the sense that many loci with additive effects are involved. The analyses performed by McGue et al. [1985], for example, although interpreted by them to indicate polygenic inheritance, really only indicate the presence of epistasis on the penetrance scale, and hence segregation at a minimum of two loci. We therefore believe that segregation and linkage analysis of schizophrenic families is not a lost cause. We further believe, perhaps in contrast to Risch, that because of the nonexperimental nature of human genetic studies, linkage will eventually provide us with the soundeset path for elucidating the genetic etiology of complex diseases.
At the outset, a distinction needs to be made between two different ways in which segregation and linkage analysis can be used to investigate the genetic etiology of complex diseases or traits. In the first approach, the phenotype for a complex trait is assumed to be adequately identified, usually as a distinct clinical entity, and we try to identify the