Recombinant DNA Studies of X Linkage in Affective Disorders

Abstract

Heredity is an important contributing factor in the vulnerability to manic-depressive illness. Family, twin, and adoption studies corroborate the genetic diathesis for the illness, but these studies do not elucidate the mode of transmission of manic-depressive psychosis.1–4 The use of linkage analysis has become widespread but has rarely been applied to psychiatric conditions. Linkage studies using color blindness and glucose-6-phosphate dehydrogenase (G6PD) deficiency as X-chromosome markers have shown that a dominant X-linked gene may be involved in the genetic transmission of a subtype of bipolar manic-depressive illness (MDI).1,5–12 The maximal lod score reported for the MDI-G6PD linkage was 4.21 at a recombination fraction of 0 = 0.06.10 However, instances of apparent father-to-son transmission of the illness have been described in family studies performed by us and by others,2,13 and data that do not support a linkage between color blindness and bipolar illness have also been reported.14 Genetic heterogeneity, as has been previously postulated for manic depression,11,15,16 could account for these apparently contradictory findings. According to this model, only a subgroup of bipolar pedigrees will show close linkage to the X chromosome and thus carry the X-linked gene, but not all bipolar illness can be X-linked. The increasing number of restriction fragment length polymorphisms (RFLPs) characterized in humans makes it possible to apply new linkage analysis using selected DNA probes.