Linkage analysis of the fragile X gene FMR-1 and schizophrenia: no evidence for linkage but report of a family with schizophrenia and an unstable triplet repeat.

We have examined 23 families multiply affected with schizophrenia for linkage to the FMR-1 gene on the X chromosome. Alleles at the FMR-1 CGG triplet repeat were analysed by the polymerase chain reaction, and methylation status at the FMR-1 locus in individuals with evidence of expanded or unstable repeats was analysed by Southern hybridization. Two-point LOD score analyses with a range of X-linked single gene models and a non-parametric affected sib-pair method revealed no evidence for linkage. In one family, however, a fragile X premutation was found, and one individual with schizophrenia and developmental delay was a mosaic for the full and premutation. We conclude that although mutations within the FMR-1 gene do not have a major aetiological role in schizophrenia in our collection of pedigrees, it is possible that FMR-1 mutations can modify the clinical phenotype of schizophrenia.