Search

Chromosome 5q33 is a region that has previously shown good evidence of linkage to schizophrenia, with four LOD scores >3.00 in independent linkage studies. We studied 450 unrelated white English, Irish, Welsh, and Scottish research subjects with schizophrenia and 450 ancestrally matched supernormal controls. Four adjacent markers at the 5' end of the Epsin 4 gene showed significant evidence of linkage disequilibrium with schizophrenia. These included two microsatellite markers, D5S1403 (P=.01) and AAAT11 (P=.009), and two single-nucleotide-polymorphism markers within the Epsin 4 gene, rs10046055 (P=.007) and rs254664 (P=.01). A series of different two- and three-marker haplotypes were also significantly associated with schizophrenia, as confirmed with a permutation test (HapA, P=.004; HapB, P=.0005; HapC, P=.007; and HapD, P=.01). The Epsin 4 gene encodes the clathrin-associated protein enthoprotin, which has a role in transport and stability of neurotransmitter vesicles at the synapses and within neurons. A genetically determined abnormality in the structure, function, or expression of enthoprotin is likely to be responsible for genetic susceptibility to a subtype of schizophrenia on chromosome 5q33.3.

Background: Previous linkage and association studies may have implicated the Dystrobrevinbinding protein 1 (DTNBP1) gene locus or a gene in linkage disequilibrium with DTNBP1 on chromosome 6p22.3 in genetic susceptibility to schizophrenia. Methods: We used the case control design to test for of allelic and haplotypic association with schizophrenia in a sample of four hundred and fifty research subjects with schizophrenia and four hundred and fifty ancestrally matched supernormal controls. We genotyped the SNP markers previously found to be significantly associated with schizophrenia in the original study and also other markers found to be positive in subsequent studies. Results: We could find no evidence of allelic, genotypic or haplotypic association with schizophrenia in our UK sample. Conclusion: The results suggest that the DTNBP1 gene contribution to schizophrenia must be rare or absent in our sample. The discrepant allelic association results in previous studies of association between DTNBP1 and schizophrenia could be due population admixture. However, even positive studies of European populations do not show any consistent DTNBP1 alleles or haplotypes associated with schizophrenia. Further research is needed to resolve these issues. The possible confounding of linkage with association in family samples already showing linkage at 6p22.3 might be revealed by testing genes closely linked to DTNBP1 for allelic association and by restricting family based tests of association to only one case per family. [ABSTRACT FROM AUTHOR]