The detection of major genes in clinical populations

Family studies have shown that psychiatric disorders are strongly familial and appear to be transmitted from parents to offspring, often over many generations. Studies of monozygotic co-twins, and adopted-away offspring have led to the conclusion that psychiatric differences between affected and unaffected individuals along with the familial aggregation suggest that there are important specific major genetic factors. New technics are being developed for the detection of major genes in patients and their relatives and these methods will lead to the delineation of new syndromes associated with specific genotypes. In this paper new approaches for detecting major loci will be described. Firstly, methods for refining the phenotype will be given. The goal of this kind of analysis is to integrate clinical, psychosocial, and biological individuals into a single study so that new phenotypes can be defined which are more homogeneous and therefore, more likely to be the consequence of unitary genetic factors. A genetic model which includes both a major locus and a multifactorial model will be described. Second, sampling schemes for selecting sub-populations of particular interest will be given. The goal of these studies is the identification of groups who have a very high risk for developing an illness. Often the study of "high density" families greatly improves the likelyhood of detecting a major gene when the disorder includes a large proportion of phenocopies. Third, the feasibility and power of genetic linkage and association studies will be discussed. This approach is becoming more important because of recent discoveries in molecular biology. Finally, the study of multigenerational, extended pedigrees developed as a method for the detection of major loci will be discussed. Since affected individuals in a single kindred may be assumed to suffer a unitary disorder, problems of heterogeneity are reduced. The utility and limitations of this approach will be reviewed.