The goal of these experiments was to understand DNA changes relevant to schizophrenia. This work compared DNA of monozygotic (MZ) twins surrounding (CAG)(n) repeating sequences, and characterized the relationship between fragile sites and schizophrenia. Twelve twin-pairs, previously classified as MZ and 18 unrelated sib-pairs, from seven families were studied. Eight twin-pairs were affected by schizophrenia, four concordantly and four discordantly. DNA comparisons were made using profiles of electrophoretic size fractionations of PCR amplified (CAG)(n) containing genomic fragments. These profiles were generated by a new method, developed by us, called targeted genomic differential display (TGDD). Surprisingly, the number of peak profile differences in MZ twin-pairs discordant for schizophrenia was greater than the concordantly ill twins and the well twins and, in some cases, overlapped the range of sib-pairs. These results might mean that some twins were not MZ but it was not possible to definitively test these samples for zygosity. Alternatively, the results might be explained as an increased mutation rate (or genomic instability) around (CAG)(n) sites in individuals afflicted with schizophrenia. Also, we uncovered an association of schizophrenia (i.e., a linkage of chromosomal abnormalities and gene localizations) with fragile sites spread throughout the genome (chi(2), P = 0.001). Furthermore, it appears that an increasing number of genes linked to schizophrenia are associated with (CAG)(n) sequences. Fragile sites and (CAG)(n) repeat sequences are known to be unstable. We speculate the association of genomic instability with schizophrenia accounts for seemingly disparate biological and environmental factors that influence disease occurrence.
Copyright 2003 Wiley-Liss, Inc.