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Family-based association testing strongly implicates DRD2 as a risk gene for schizophrenia in Han Chinese from Taiwan

Molecular Psychiatry volume 14, pages 885–893 (2009)Cite this article

Abstract

The gene that codes for dopamine receptor D2 (DRD2 on chromosome 11q23) has long been a prime functional and positional candidate risk gene for schizophrenia. Collectively, prior case–control studies found a reliable effect of the Ser311Cys DRD2 polymorphism (rs1801028) on risk for schizophrenia, but few other polymorphisms in the gene had ever been evaluated and no adequately powered family-based association study has been performed to date. Our objective was to test 21 haplotype-tagging and all three known nonsynonymous single-nucleotide polymorphisms (SNPs) in DRD2 for association with schizophrenia in a family-based study of 2408 Han Chinese, including 1214 affected individuals from 616 families. We did not find a significant effect of rs1801028, but we did find significant evidence for association of schizophrenia with two multi-marker haplotypes spanning blocks of strong linkage disequilibrium (LD) and nine individual SNPs (Ps<0.05). Importantly, two SNPs (rs1079727 and rs2283265) and both multi-marker haplotypes spanning entire LD blocks (including one that contained rs1801028) remained significant after correcting for multiple testing. These results further add to the body of data implicating DRD2 as a schizophrenia risk gene; however, a causal variant(s) in DRD2 remains to be elucidated by further fine mapping of the gene, with particular attention given to the area surrounding the third through fifth exons.

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Acknowledgements

This work was supported in part by a Young Investigator Award from NARSAD, The Mental Health Research Association (SJG), a research project grant (1R01MH059624) from the United States National Institute of Mental Health (MTT) and grants (90-8825PP and 91,92-9113PP) from the National Health Research Institute of Taiwan and the Genomic Medicine Research Program of Psychiatric Disorders of National Taiwan University Hospital. We thank Allison Brown and Maura Regan at the HPCGG for coordinating and performing the genotyping for this project, Sharon Chandler at UCSD for technical assistance, Frank Middleton at SUNY Upstate Medical University for assistance with detecting pedigree inconsistencies and Mendelian errors and Vural Ozdemir at the University of California, Irvine, for critical reading and editing of the manuscript. We further thank our research and clinical collaborators in the Taiwan Schizophrenia Linkage Study Group, including Chih-Min Liu, Wei J Chen, Ming-Ming Tsuang, Shih-Kai Liu, Ming-Hsien Shieh, Tzung-Jeng Hwang, Wen-Chen Ou-Yang, Chun-Ying Chen, Chwen-Cheng Chen, Jin-Jia Lin, Frank Huang-Chih Chou, Ching-Mo Chueh, Wei-Ming Liu, Mei-Hua Hall, Chiao-Chicy Chen, Jia-Jiu Lo, Jia-Fu Lee, Seng Shen, Yung Feng, Shin-Pin Lin, Shi-Chin Guo, Ming-Cheng Kuo, Liang-Jen Chuo, Chih-Pin Lu, Deng-Yi Chen, Huan-Kwang Ferng, Nan-Ying Chiu, Wen-Kun Chen, Tien-Cheng Lee, Hsin-Pei Tang, Yih-Dar Lee, Wu-Shih Wang, For-Wey Long, Tiao-Lai Huang, Jung-Kwang Wen, Cheng-Sheng Chen, Wen-Hsiang Huang, Shu-Yu Yang and Cheng-Hsing Chen. Finally, we thank the hospitals that participated in this study, including National Taiwan University Hospital and Medical College of National Taiwan University, National Taoyuan Psychiatric Center, National Tsaotun Psychiatric Center, National Cheng-Kung University, Kai-Suan Psychiatric Hospital of Kaohsiung City, Yu-Li Veterans Hospital and National Yu-Li Hospital.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, and Medical Genetics Research Center, SUNY Upstate Medical University, Syracuse, NY, USA

    S J Glatt, S V Faraone & J A Lasky-Su

  2. Department of Psychiatry, Center for Behavioral Genomics, University of California, San Diego, La Jolla, CA, USA

    T Kanazawa & M T Tsuang

  3. Department of Neuropsychiatry, Osaka Medical College, Osaka, Japan

    T Kanazawa

  4. Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    H-G Hwu

  5. Department of Psychiatry, Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan

    H-G Hwu

  6. Department of Psychology, College of Science, National Taiwan University, Taipei, Taiwan

    H-G Hwu

  7. Harvard Departments of Epidemiology and Psychiatry, Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA, USA

    M T Tsuang

  8. Veterans Affairs San Diego Healthcare System, San Diego, CA, USA

    M T Tsuang

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  1. S J Glatt
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Correspondence to S J Glatt.

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

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Glatt, S., Faraone, S., Lasky-Su, J. et al. Family-based association testing strongly implicates DRD2 as a risk gene for schizophrenia in Han Chinese from Taiwan. Mol Psychiatry 14, 885–893 (2009). https://doi.org/10.1038/mp.2008.30

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