Is the histidine triad nucleotide-binding protein 1 (HINT1) gene a candidate for schizophrenia?

background: The histidine triad nucleotide-binding protein 1, HINT1, hydrolyzes adenosine 5'-monophosphoramidate substrates such as AMP-morpholidate. The human HINT1 gene is located on chromosome 5q31.2, a region implicated in linkage studies of schizophrenia. HINT1 had been shown to have different expression in postmortem brains between schizophrenia patients and unaffected controls. It was also found to be associated with the dysregulation of postsynaptic dopamine transmission, thus suggesting a potential role in several neuropsychiatric diseases.

methods: In this work, we studied 8 SNPs around the HINT1 gene region using the Irish study of high density schizophrenia families (ISHDSF, 1350 subjects and 273 pedigrees) and the Irish case control study of schizophrenia (ICCSS, 655 affected subjects and 626 controls). The expression level of HINT1 was compared between the postmortem brain cDNAs from schizophrenic patients and unaffected controls provided by the Stanley Medical Research Institute.

results: We found nominally significant differences in allele frequencies in several SNPs for both ISHDSF and ICCSS samples in sex-stratified analyses. However, the sex effect differed between the two samples. In expression studies, no significant difference in expression was observed between patients and controls. However, significant interactions amongst sex, diagnosis and rs3864283 genotypes were observed.

conclusion: Data from both association and expression studies suggested that variants at HINT1 may be associated with schizophrenia and the associations may be sex-specific. However, the markers showing associations were in high LD to the SPEC2/PDZ-GEF2/ACSL6 locus reported previously in the same samples. This made it difficult to separate the association signals amongst these genes. Other independent studies may be necessary to distinguish these candidate genes.