Association study of an SNP combination pattern in the dopaminergic pathway in paranoid schizophrenia: a novel strategy for complex disorders

Abstract

Schizophrenia is a common mental disorder with a complex pattern of inheritance. Despite a large number of studies in the past decades, its molecular etiology remains unknown. In this study, we proposed a 'system-thinking' strategy in seeking the combined effect of susceptibility genes for a complex disorder by using paranoid schizophrenia as an example. We genotyped 85 reported single-nucleotide polymorphisms (SNPs) present in 23 genes for the dopamine (DA) metabolism pathway among 83 paranoid schizophrenics and 108 normal controls with detailed clinical and genetic information. We developed two novel multilocus approaches-the potential effective SNP combination pattern and potential effective dynamic effects analysis, by which three susceptibility genotype combinations were found to be associated with schizophrenia. These results were also validated in a family-based cohort consisting of 95 family trios of paranoid schizophrenia. The present findings suggest that the COMT and ALDH3 combination may be the most common type involved in predisposing to schizophrenia. Since the combination blocks the whole pathways for the breakdown of DA and noradrenaline, it is very likely to play a central role in developing paranoid schizophrenia.

Expression and initial characterization of human ALDH3B1

“…Further investigation of the ALDH3B1 intronic SNP, its potential connection to isoform b and significance in schizophrenia is necessary in order to draw any conclusions. The ALDH3B1 SNP genotype has been proposed to be associated with schizophrenia through an alteration in dopamine metabolism [6]. While our findings indicate that ALDH3B1 is present in the brain, the dopamine-derived aldehyde, DOPAL, seems to be a poor substrate.…”

Genetic tests of biologic systems in affective disorders

“…However, it is also conceivable that not individual genes but abnormalities in several genes within a system or in several neuronal, neural, or hormonal systems are implicated in the functional hypotheses for etiology of affective disorders. Analysis of entire systems examining a same sample set has only rarely been undertaken, 11,12 and examples of definitive success have yet to be seen. At this time, analysis of a well-chosen and comprehensive set of candidate genes, with the support of informatics analysis of the genomic structure of each gene, may yield successful detection of specific genes and pathways associated with illness.…”

Screening study for genetic polymorphisms affecting pharmacokinetics of simvastatin

“…Recent studies have linked SNPs at the ALDH3B1 locus to the development of paranoid schizophrenia. [26][27][28] In this study, major allele homozygotes (G) of rs2286168 of ALDH3B1 might be associated (P = 4.120x10 -4 and P = 9.759x10 -6 , in additive and dominant models, respectively; Table 3) with decreased absorption of simvastatin. ABCC4 encodes MRP4, a member of the ATP-binding cassette family of membrane transporters involved in the efflux of endogenous and xenobiotic molecules.…”