Folate-sensitive fragile sites in schizophrenia and bipolar disorder: Candidate regions for susceptibility loci?

The discovery of trinucleotide repeat expansion as a disorder-causing mutation mechanism in >10 conditions associated with neurodevelopmental abnormalities and/or neurodegeneration provides an alternative to candidate gene testing and linkage studies to search for genes of major effect in neuropsychiatric disorders. Based on the finding that five rare folate-sensitive chromosomal fragile sites have been shown to result from large expansions of CGG-repeats which have been methylated, we compared expression of fragile sites in subjects with schizophrenia (N = 20), bipolar disorder (N = 25), and unipolar disorder (N = 19) with that in controls. Seven recognized rare folate-sensitive fragile sites were seen significantly more frequently in the patient groups compared to controls (Fisher's exact test, 1-tailed, P = 0.0365-<0.0001) for the different fragile sites. Two fragile sites (chromosomes 11 and 12) were seen in both schizophrenic and bipolar patients, and two (chromosome 11) were seen in both unipolar and bipolar patients. A fragile site on chromosome 22, located near COMT and the velo-cardio-facial critical region, was seen in three schizophrenic subjects and none of the other patients or controls and is of particular interest given the positive linkage to this region in some families with schizophrenia and the association of psychiatric problems in some individuals with velo-cardio-facial syndrome and an interstitial deletion at 22q11. Cloning of these fragile sites and testing CGG-repeat sequences within the regions for expansion in schizophrenia, bipolar disorder, and unipolar disorder will be the ultimate test of the hypothesis that these fragile sites are located at genes involved in the pathogenesis of these conditions.