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

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Abstract

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.

Introduction

Schizophrenia is a severe psychiatric disorder characterized by a complex mode of inheritance. Family linkage studies and studies of chromosomal abnormalities associated with schizophrenia have identified a number of schizophrenia susceptibility loci (Lewis et al., 2003). Our group has found promising linkages at 5q21-31, 6p25-24, 6p23, 8p22-21 and 10p15-p11 in the Irish Study of High Density Schizophrenia Families(ISHDSF) (Straub et al., 2002). These linkage regions had also been reported by several other groups (Lewis et al., 2003, Schwab et al., 2000). In our previous fine-mapping of the linkage peak at 5q21-31 with the ISHDSF sample, we found that a 758 kb interval coding for the SPEC2/PDZ-GEF2/ACSL6 gene was associated with schizophrenia (Chen et al., 2006). Markers in this area show sex-specific associations with schizophrenia. Telomeric to this area, we also found that interleukin 3 (IL3) gene, which is in a head-to-head orientation to ACSL6, is associated with schizophrenia in our Irish family and case control samples (Chen et al., 2007a). The histidine triad nucleotide-binding protein 1 (HINT1) gene is located immediately centromeric (about 194 kb) to the SPEC2/PDZ-GEF2/ACSL6 locus. In the fine-mapping study, we observed that several markers in the vicinity of HINT1 showed nominal significance (Chen et al., 2006).

The HINT1 gene is an ubiquitous member of the histidine triad (HIT) protein family characterized by the presence of a conserved HIT sequence motif (Klein et al., 1998). The human HINT1 gene is about 6 kb in length, containing 3 exons (Fig. 1). HINT1 has tumor suppressor function through inhibiting transcription factor AP-1 activity by binding to a POSH-JNK2 complex, thus inhibiting the phosphorylation of c-Jun (Wang et al., 2007), or by interacting with Pontin and Reptin and inhibiting TCF-beta-catenin-mediated transcription (Welske and Huber, 2005). HINT1 protein is widely expressed in mammalian brains including the mesocorticolimbic and mesostriatal regions. Weitzdoerfer et al. (2001) reported significant reduction of HINT1 protein in fetal brains of Down Syndrome patients. In microarray expression studies, Vawter et al. (2002) reported decreased mRNA expressions of HINT1 in the dorsolateral prefrontal cortex of schizophrenia patients. These differences were confirmed by real time quantitative polymerase chain reaction (Q-PCR) and in situ hybridization (Vawter et al., 2004). In that study, male subjects with schizophrenia had lower expression than male controls. Using HINT1 knockout mice, Wang et al. reported that systemic administration of apomorphine, a dopamine receptor agonist, significantly increased locomotor activity in HINT1 knockout mice, suggesting that postsynaptic dopamine function may be altered in these animals (Wang et al., 2006). Furthermore, the authors indicated that the absence of HINT1 protein may be associated with the dysregulation of postsynaptic dopamine transmission. In view of the documented link between dopamine transmission and schizophrenia, they suggested the possible involvement of HINT1 in the pathophysiology of the disease. All these studies suggest that HINT1 is a plausible candidate gene for schizophrenia. To define the centromeric boundary of the association signals observed in the SPEC2/PDZ-GEF2/ACSL6 region we performed association and expression studies of the HINT1 gene.

Section snippets

The ISHDSF sample

The ISHDSF was collected in Northern Ireland, United Kingdom and the Republic of Ireland. The sample contained 273 pedigrees and about 1350 subjects had DNA sample for genotyping. Historically, the ISHDSF sample had multiple disease definitions reflecting the probable genetic relationship of the syndromes to classic schizophrenia. In this study, we used the narrow definition, which includes schizophrenia, poor-outcome schizoaffective disorder and simple schizophrenia according to DSM-III

LD and haplotype structure

We examined the LD and haplotype structure for both ISHDSF and ICCSS with the HAPLOVIEW program. In both samples, most markers shared high LD with each other, but only markers 1–5 were grouped in a single LD block. The overall pattern of the two samples was similar (Fig. 2).

Association analyses of the ISHDSF sample

Marker information and allele frequencies were presented in Table 2. The genotype frequencies of all 8 markers studied were in accordance with the Hardy–Weinberg equilibrium (HWE). Using the PDT to examine the associations,

Discussion

Multiple linkage studies have implicated chromosome 5q21-33, where HINT1 is located, as a region likely to harbor risk genes (Schwab et al., 1997), including the study of ISHDSF (Straub et al., 1997, Straub et al., 2002). Gene expression of HINT1 in prefrontal cortex was found to decrease in schizophrenia and male patients has lower level expression of HINT1 (Vawter et al., 2002, Vawter et al., 2004). Recently HINT1 was also suggested to be associated with dysregulation of postsynaptic dopamine

Role of funding source

The sponsors (National Institute of Mental Health and National Alliance for Research on Schizophrenia and Depression) played no roles in the study design, sample collection, data analysis and interpretation and the preparation of this manuscript.

Contributors

XC conceived and designed the study. QC conducted the experiment, data analysis and drafted the manuscript. XW performed genotyping. FAO, DW and KSK collected the DNA samples and performed the clinical diagnostic interviews. All authors contributed to and approved the final manuscript.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

This study is supported by a research grant (RO1MH41953) to KSK from National Institute of Mental Health and by a young investigator award to XC from the National Alliance for Research on Schizophrenia and Depression. We thank the patients and their families for participating in this study. The postmortem brain cDNA specimens were donated by The Stanley Medical Research Institute Brain Collection courtesy of Drs. Michael B. Knable, E. Fuller Torrey, Maree J. Webster, and Robert H. Yolken.

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