These findings add further support to our previous report in that the SNP rs9843659 in the SAP97
gene is genetically associated with male patients with schizophrenia. The allele C of this SNP conferred a risk for schizophrenia susceptibility in both studies. As replicating results of a genetic association study in independent samples is considered as a standard to demonstrate the relevance of a candidate gene [19
], the results of the present study in conjunction with the previous study strongly support the view that SAP97
is a risk gene for male patients with schizophrenia.
In the most recent and largest genome-wide association studies (GWAS), the tag SNP rs1392705 on chromosome 3q29 closest to the SNP rs9843659 in the SAP97
gene demonstrated a nominal genome-wide significance (p = 8.45 × 10-4
]. Another genome-wide analysis of the copy-number variation (CNV) found a statistically significant excess of deletions in schizophrenia at 3q29 [23
]. The telomeric breakpoint of the minimal deletion in this study was 4.7 kb from the transcriptional stop of the SAP97
gene. These findings also implicate SAP97
as a candidate gene for schizophrenia susceptibility.
The contributions of the rs9843659 polymorphism to the development of schizophrenia remains unexplained because 1) this SNP is found in the fourth large intron, but not in the exons that encode the amino acid sequences of the SAP97 protein including the functional domains and motifs, and 2) as previously described, bioinformatics tools we used failed to reveal any consensus sequences in the intron part that may play a role in the alternative promoter use or alternative splicing. The rs9843659 polymorphism could cause certain modifications in the regulation of transcription or translation of the SAP97
gene by an unidentified mechanism, for instance, a change in its higher-order genome structure. This type of a 'silent' SNP has indeed been observed to alternate substrate specificity in the Multidrug Resistance 1 (MDR1
) gene [24
From this view point, it is of interest to note that the expressional changes of the SAP97 proteins have been reported by two independent research groups in the dorsolateral prefrontal cortex of postmortem schizophrenic brains [25
]. However, it is not totally excluded that these results might be due to long-term treatment with antipsychotic drugs [25
] and another research group failed to observe any significant alteration in the SAP97 mRNA level in the cortical area [27
]. Furthermore, animal experiments have revealed the mutual interactions between SAP97 and the NMDA receptor that is hypothesized to be dysfunctional in schizophrenia brains. Thus, the SAP97
gene knockdown reduced the surface expression of GluR1 and GluR2 and inhibited both the AMPA and NMDA excitatory postsynaptic currents (EPSCs) [28
], and the NMDA antagonists upregulated the SAP97
mRNA expression in the cerebral cortex [14
]. A more recent in vitro
study using transfection, viral infection, small interference RNA, and antisense oligonucleotide techniques has demonstrated in the rat prefrontal cortex a functional link of the SAP97 proteins with the D4 type dopamine receptor that is possibly aberrant in mental illnesses including schizophrenia [29
]. Taken together, the presumed dysregulation of the SAP97
gene connected to the rs9843659 polymorphism could lead to the plausible NMDA receptor deficits and/or abnormal dopamine neurotransmission in patients with schizophrenia.
The replicated male-selective genetic association of SAP97
gene with schizophrenia appears to be in line with the data indicating the sex-specific genetic associations with the disorder reported in several genes such as Disrupted-In-Schizophrenia 1 (DISC1
), reelin (RELN
) and D-amino acid oxidase (DAO
]. These phenomena might be related to the well-known gender differences in schizophrenia [33
] that, for instance, include the clinical observations that male patients tend to exhibit an earlier onset and severer course than female patients, although the genetic basis of the sex-differences in schizophrenia remains unclear. Consequently, the male-specific association seen in the SAP97
gene could produce different influences on the putative disturbed neurotransmission via the NMDA receptor between male and female patients with schizophrenia.