No association of the -277A variant allele of the UFD1L promoter polymorphism and schizophrenia

Background: Velo-cardio-facial syndrome (VCFS), a syndrome characterized by distinctive dysmorphology, congenital heart disease and schizophrenia, is associated with small interstitial deletions of chromosome 22q11. While the majority of VCFS individuals have a common ∼ 3Mb deletion, people with smaller deletions have also been reported. The gene UFD1L has been proposed as a candidate for VCFS and schizophrenia in VCFS because: a) it maps to the commonly deleted region, b) it is developmentally expressed in the medial telencephalon that forms the hippocampus, c) Yamagishi et al found the gene deleted in 181 of 182 22q11 deleted patients with the re maining patient possessing a unique 20kb deletion that removed exons 1 to 3 and d) De Luca et al described a functional promoter polymorphism of UFD1L which was shown to be associated with schizophrenia in their sample In this study, we have detected and characterized the same polymorphism within the UFD1L promoter and genotyped it through two association studies. Method: The VCFS sample comprised 49 adults with VCFS of which 24% (n = 12) fulfilled DSM-IV criteria for schizophrenia. The schizophrenia association sample consisted of 180 unrelated patients with DSM-IV schizophrenia and 183 control subjects matched for age, sex and ethnicity. We amplified the promoter region of UFD1L (-33 to -483) and screened 14 schizophrenic patients using dHPLC heteroduplex analysis. We detected a G A polymorphism at position -277 and designed an RFLP assay using Sea I. Results: The frequency of the -277A variant allele in our VCFS - Schizophrenic group was 0.40 compared to 0.34 in the unaffected VCFS group - 2 = 0.726, p= >0.50. For the Schizophrenia case control study the allele frequencies for the -277A allele were- patients 0.49 and controls 0.50 2=0.213 and p= >0.50. Conclusions: We found no evidence to associate the -277A allele of the UFD1L promoter polymorphism with increased risk of schizophrenia in either our VCFS group or in a case control study. However we cannot exclude the possibility that this polymorphism may be an important risk factor in other populations or that our sample was not large enough to detect a gene of small effect.