Although genome-wide scan for linkage in multiply-affected families with schizophrenia has consumed lots of money and effort, no forms of schizophrenia following Mendelian inheritance patterns have yet been discovered [2
]. Numerous evidences show that multiple genes of small effect contribute to increasing liability to SZ, which seems to have a cumulative effect, and putatively, threshold effect. On the other hand, the study on schizophrenia has confirmed the vital role of genes in its etiology, but has not so far identified the relationship between observed genetic risks and specific DNA variants, protein alterations, or biological processes [18
], nor was diagnostic neuropathology, or even unequivocally replicated associations with the same alleles or haplotype within each gene identified [4
Meta-analyses of SZ linkage studies have provided evidence of susceptibility in chromosomes 2p, 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, 22q, and 14p [2
], some of which are strong enough to withstand rigorous correction for whole genome analysis (e.g. 1q, 6p, 6q, 15q) [19
]. Recently, many polymorphisms located in regions of chromosome 1 were reported as susceptibility loci for SZ [5
], including risk markers in 1q44 [21
] 1q43 [22
], both of which lie adjacent to ADSS.
Although whole genome linkage scan and functional studies have implied several very promising positional candidates, such as NRG1 [23
], DTNBP1 [24
], COMT [4
], DISC1 [25
], DAOA [26
], RGS4 [28
] and so on [5
], there may be several genes that play subtle or weak roles in the pathogenesis of SZ, making it difficult to investigate by traditional approaches. To tackle this problem, another approach to finding potential candidate genes is using microarray technology to examine RNA of a gene which shows differential expression between patients and controls, by which ADSS gene was suggested as one of candidates for SZ.
Functionally, the ADSS catalyzes the key step in the synthesis of AMP, which influences the energy metabolism through the purine nucleotide cycle (PNC) and the AMPK (AMP-activated protein kinase) pathway [32
]. The reaction is as follows: IMP+L-aspartate+GTP ↔ adenylosuccinate+GDP+phosphate. Genetically, ADSS gene resides in the susceptibility loci and the blood-derived RNA of ADSS was among the eight genes with putatively differential diagnostic power for SZ. Hereto, there is no genetic association study of ADSS with SZ, and the mechanism of hypo-expression of ADSS is elusive, nevertheless, it suggested that ADSS gene was possibly involved in the genetic architecture of SZ, for genetic variation or polymorphisms can dominate gene expression as well as confer disease risk to human beings.
Our study is an exploration study to seek the trait's genetic basis following a clue from RNA alterations in SZ. However, the data did not display any statistically significant difference for both the allelic and genotypic distribution between cases and controls. Although haplotype analysis is a powerful tool for identifying candidate genes for complex disease, there was no positive finding in current study. Therefore, our result does not support the association of ADSS gene with SZ. It implies that down-regulation of ADSS in patients may not result from the gene's polymorphisms.
One common issue in the study of complex diseases is the limited sample size, resulting in inadequate power to detect association. With regard to our data, assuming the frequency of risk allele in controls to be 0.5, our sample of 480 cases and 502 controls is able to detect an odds ratio (OR) of 1.43 or above with 80% power [33
]. It is possible that false-negative results may arise from lack of power. Another issue of researches in multifactor diseases is the underlying high degree of genetic heterogeneity of perplexing phenotype. SZ is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determine the genetic vulnerability of an individual. Thus, there are likely different genes or sets of genes associated with schizophrenia disorders in different populations [34
]. It is necessary to validate or replicate our association results using independent samples especially from other ethnic populations.
It's been suggested that the promoter and 5' flanking region of murine ADSS gene possessed regulatory elements that could influence its expression [35
]. In addition, ADSS has several splicing variants. Therefore, the examinations of SNPs within 5' flanking region and those potentially affecting splicing may be valuable in further study.