Evidence for familial cosegregation of major affective disorder and genetic markers flanking the gene for Darier's disease

Darier's disease is a rare autosomal dominantly inherited keratosis.(1) We have previously reported a family in which major affective disorder co-segregated with Darier's disease, consistent with linkage between the Darier gene and a susceptibility locus for affective illness (max lod = 2.1).(2) The Darier gene has been mapped to 12q 23-q24.1 and identified as ATP2A2, a gene encoding SERCA2-a sarcoplasmic/encloplasmic reticulum calcium pump that plays a role in intracellular calcium signalling.(3) A number of groups have reported independent evidence of linkage between bipolar disorder and markers in this region.(4) We here describe a further Caucasian family of European origin in which there is co-occurrence of Darier's disease and major affective disorder including bipolar disorder and report the results of linkage analysis employing genetic markers flanking the Darier's gene. The pedigree includes two individuals with mood disorder from a branch of the family not affected with Darier's disease. However, there is a new mutation in the Darier (ATP2A2) gene in this family and all individuals affected by mood disorder show co-segregation with a haplotype In the region of the Darier's gene (max lod = 3.58). The family provides strong evidence against the Darier-causing mutation itself playing a major role in affective disorder but strongly supports the existence of a bipolar disorder susceptibility gene in the Darier region.