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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.

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Acknowledgements

We thank Michael Zhang, Jinhua Wang and Siqing Chen for valuable discussions and a critical reading of this manuscript, and the patients and their families whose participation made this project possible. This project was supported by the grants from the National High Technology Research and Development Program of China (Grant No. 2001AA221071), the National Natural Science Foundation of China (Grant Nos. 39625007 and 39993420), the China Nation Key Program on Basic Research (Grant No. 1998051003), the National Key Technology Research and Development Program of China (Grant No. 2002BA711A07).

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Correspondence to Y Shen.

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(Supplementary information accompanies the paper on Molecular Psychiatry website (http://www.nature.com/mp))

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Xu, Q., Jia, YB., Zhang, BY. et al. Association study of an SNP combination pattern in the dopaminergic pathway in paranoid schizophrenia: a novel strategy for complex disorders. Mol Psychiatry 9, 510–521 (2004). https://doi.org/10.1038/sj.mp.4001472

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