The genetic implications of age-dependent penetrance in manic-depressive illness.

THE DISCOVERY by ANGT+” and PERRIS’ that manic-depressive illness (MDI) is genetically different from unipolar depression has led to renewed interest in the genetic predisposition to to MDI. WINOKUR~-5 and his collaborators proposed a sex-linked dominant (SLD) mode of of inheritance, on the basis of familial transmission patterns in 61 pedigrees and on the basis of apparent linkage with X-chromosomal markers.‘j As expected with sex-linkage, fatherson transmission was not observed, but all other forms of parent-child transmission were commonly encountered. This finding was strengthened by the observation that affected sisters of female probands outnumbered affected brothers, while the sex-ratio among sibs of male probands was essentially unity. WINOKUR~ extended the series by 28 pedigrees, and obtained the same patterns as found in the initial series. TAYLOR and ABRAM@, reporting a series of 50 pedigrees, essentially corroborated all of Winokur’s findings in their 20 early onset patients (onset <30), but encountered a single case of father-son transmission in the late onset (>30) group. HELZER and WINKOUR studied the pedigrees of an additional 30 male probands, and found one case of father-son transmission. These rare cases of fatherson transmission are entirely compatible with the SLD hypothesis, because one would expect an occasional affected father to be married to an unaffected female carrier. Other workers, however, have reported quite contradictory results. PERRIS~ and ANGST’ failed to find sex-ratios suggestive of sex-linkage, and moreover Perris encountered 13 instances of father-son transmission in 138 kindreds. GOETZL et al.11 have reported comparable results, with four cases of father-son transmission among 39 pedigrees. JAMES and CHAPMAN~~ and VON GRIEFF et al.13 have also reported several cases of father-son transmission. The frequency of father-son transmission is too high in these studies for a rare sex-linked dominant, and sex-ratios are more suggestive of an autosomal dominant (AD) than of a sex-linked dominant (SLD). MENDLEWICZ and RAINER14 report sex-ratios similar to these of WINOKUR et al.“, but also report 10 cases of father-son transmission in a series of 134 kindreds. From this same series, however, MENDLEWICZ and FLEISS’S isolated several