Original Research Article

Molecular Psychiatry (2004) 9, 510–521. doi:10.1038/sj.mp.4001472 Published online 27 January 2004

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

Q Xu1,2, Y-B Jia1,2, B-Y Zhang1,2, K Zou1,2, Y-B Tao1,2, Y-P Wang1,2, B-Q Qiang1,2, G-Y Wu1, Y Shen1,2, H-K Ji3, Y Huang3, X-Q Sun3, L Ji3, Y-D Li3, Y-B Yuan4, L Shu4, X Yu4, Y-C Shen4, Y-Q Yu5 and G-Z Ju5 Chinese Schizophrenia Consortium*

  1. 1National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS), Peking Union Medical College (PUMC), Beijing, China
  2. 2National Center of Human Genome Research, Beijing, China
  3. 3The Ministry of Education (MOE) Key Laboratory of Bioinformatics, State Key Laboratory of Intelligent Technology and Systems, Department of Automation, Tsinghua University, Beijing, China
  4. 4Peking University Institute of Mental Health, Beijing, China
  5. 5Jilin University Research Center for Genomic Medicine, National Center of Human Genome Research, Changchun, Jilin, China

Correspondence: Professor Y Shen, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS), Peking Union Medical College (PUMC), Beijing 100005, China. E-mail: sheny@ms.imicams.ac.cn; L Ji, E-mail: zc_sa@mail.tsinghua.edu.cn; Y-C Shen, E-mail: shenyc@public.bta.net.cn

*Chinese Schizophrenia Consortium:
Group 1: Qi Xu1,2 Yan-Bin Jia1,2 Bo-Yu Zhang1,2 Ke Zou1,2 Yu-Bin Tao1,2 Yan-Ping Wang1,2 Bo-Qin Qiang1,2 Guan-Yun Wu1 and Yan Shen1,2
Group 2: Hong-Kai Ji3 Ying Huang3 Xiang-Qing Sun3 Liang Ji3 and Yan-Da Li3
Group 3: Yan-Bo Yuan4 Liang Shu4 Xin Yu4 and Yu-Cun Shen4
Group 4: Ya- Qin Yu5 Gui-Zhi Ju5 Shu-Zheng Liu5 and Jie-Ping Shi5
These four groups contributed equally to this work

Received 23 July 2003; Revised 2 October 2003; Accepted 28 October 2003; Published online 27 January 2004.



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.


schizophrenia, complex disorder, susceptibility genotype combinations, single nucleotide polymophism, dopamine metabolic pathway, clinial subgroup, effective SNP combination pattern, potential effective dynamic effects



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