The outlook for linkage research in psychiatric disorders

Analysis of the distribution of diagnoses in families (segregation analysis) has not, so far, advanced us toward the goal of resolving the inheritance of the major psychiatric disorders. Recent advances in genetics, particularly the development of new molecular genetic linkage methods, have made it, at least theoretically, feasible to scan the entire human genome, so that in a properly designed and executed set of studies it will be possible to demonstrate whether there exists single locus transmission for a particular disorder, and to map the locus. We present here an analysis of feasibility of moderate-sized pedigrees (approximately 15 persons, two generations) and affected-sib-pair sets in such studies. Eight to ten moderate-sized pedigrees are sufficient to perform definitive mapping under the tested conditions, of recessive or additive inheritance, low penetrance of the heterozygote, and a genetically homogeneous disorder. The affected-sib-pair method required 25 pairs of sibs to detect linkage under such conditions in a recessive model, and 45 in a dominant model. When there is genetic heterogeneity, moderate-sized pedigrees are much less useful, but the affected-sib-pair method retains considerable power.