Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples

Molecular Psychiatry volume 21, pages 975–982 (2016)Cite this article

Subjects

Abstract

The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Sullivan PF, Kendler KS, Neale MC . Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003; 60: 1187–1192.

    Article  Google Scholar 

  2. Seeman P . Dopamine D2 receptors as treatment targets in schizophrenia. Clin Schizophr Relat Psychoses 2010; 4: 56–73.

    Article  Google Scholar 

  3. Bertolino A, Blasi G . The genetics of schizophrenia. Neuroscience 2009; 164: 288–299.

    Article  CAS  Google Scholar 

  4. Allen NC, Bagade S, McQueen MB, Ioannidis JP, Kavvoura FK, Khoury MJ et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet 2008; 40: 827–834.

    CAS  Google Scholar 

  5. Zhang Y, Bertolino A, Fazio L, Blasi G, Rampino A, Romano R et al. Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc Natl Acad Sci USA 2007; 104: 20552–20557.

    Article  CAS  Google Scholar 

  6. Blasi G, Lo Bianco L, Taurisano P, Gelao B, Romano R, Fazio L et al. Functional variation of the dopamine D2 receptor gene is associated with emotional control as well as brain activity and connectivity during emotion processing in humans. J Neurosci 2009; 29: 14812–14819.

    Article  CAS  Google Scholar 

  7. Frank MJ, Hutchison K . Genetic contributions to avoidance-based decisions: striatal D2 receptor polymorphisms. Neuroscience 2009; 164: 131–140.

    Article  CAS  Google Scholar 

  8. Bertolino A, Fazio L, Caforio G, Blasi G, Rampino A, Romano R et al. Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia. Brain 2009; 132: 417–425.

    Article  Google Scholar 

  9. Bertolino A, Taurisano P, Pisciotta NM, Blasi G, Fazio L, Romano R et al. Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance. PLoS One 2010; 5: e9348.

    Article  Google Scholar 

  10. Sambataro F, Fazio L, Taurisano P, Gelao B, Porcelli A, Mancini M et al. DRD2 genotype-based variation of default mode network activity and of its relationship with striatal DAT binding. Schizophr Bull 2013; 39: 206–216.

    Article  Google Scholar 

  11. Fazio L, Blasi G, Taurisano P, Papazacharias A, Romano R, Gelao B et al. D2 receptor genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans. Neuroimage 2011; 54: 2915–2921.

    Article  CAS  Google Scholar 

  12. Blasi G, Napolitano F, Ursini G, Taurisano P, Romano R, Caforio G et al. DRD2/AKT1 interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia. Proc Natl Acad Sci USA 2011; 108: 1158–1163.

    Article  CAS  Google Scholar 

  13. Di Giorgio A, Smith RM, Fazio L, D'Ambrosio E, Gelao B, Tomasicchio A et al. DRD2/CHRNA5 interaction on prefrontal biology and physiology during working memory. PLoS One 2014; 9: e95997.

    Article  Google Scholar 

  14. Glatt SJ, Faraone SV, Lasky-Su JA, Kanazawa T, Hwu HG, Tsuang MT . Family-based association testing strongly implicates DRD2 as a risk gene for schizophrenia in Han Chinese from Taiwan. Mol Psychiatry 2009; 14: 885–893.

    Article  CAS  Google Scholar 

  15. Zheng C, Shen Y, Xu Q . Rs1076560, a functional variant of the dopamine D2 receptor gene, confers risk of schizophrenia in Han Chinese. Neurosci Lett 2012; 518: 41–44.

    Article  CAS  Google Scholar 

  16. Lange C, DeMeo D, Silverman EK, Weiss ST, Laird NM . PBAT: tools for family-based association studies. Am J Hum Genet 2004; 74: 367–369.

    Article  Google Scholar 

  17. Glatt SJ, Jonsson EG . The Cys allele of the DRD2 Ser311Cys polymorphism has a dominant effect on risk for schizophrenia: evidence from fixed- and random-effects meta-analyses. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 149–154.

    Article  Google Scholar 

  18. Weickert CS, Sheedy D, Rothmond DA, Dedova I, Fung S, Garrick T et al. Selection of reference gene expression in a schizophrenia brain cohort. Aust NZ J Psychiatry 2010; 44: 59–70.

    Article  Google Scholar 

  19. Deng C, Weston-Green KL, Han M, Huang X-F . Olanzapine treatment decreases the density of muscarinic M2 receptors in the dorsal vagal complex of rats. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 915–920.

    Article  CAS  Google Scholar 

  20. Shah NB, Duncan TM . Bio-layer interferometry for measuring kinetics of protein-protein interactions and allosteric ligand effects. J Vis Exp 2014; 84: e51383.

    Google Scholar 

  21. Piva F, Giulietti M, Burini AB, Principato G . SpliceAid 2: a database of human splicing factors expression data and RNA target motifs. Hum Mutat 2012; 33: 81–85.

    Article  CAS  Google Scholar 

  22. Arinami T, Itokawa M, Enguchi H, Tagaya H, Yano S, Shimizu H et al. Association of dopamine D2 receptor molecular variant with schizophrenia. Lancet 1994; 343: 703–704.

    Article  CAS  Google Scholar 

  23. Vercammen A, Weickert CS, Skilleter AJ, Lenroot R, Schofield PR, Weickert T . Common polymorphisms in dopamine-related genes combine to produce a “schizophrenia-like” prefrontal hypoactivity. Transl Psychiatry 2014; 4: e356.

    Article  CAS  Google Scholar 

  24. Verga M, Macciardi F, Pedrini S, Cohen S, Smeraldi E . No association of the Ser/Cys311 DRD2 molecular variant with schizophrenia using a classical case control study and the haplotype relative risk. Schizophr Res 1997; 25: 117–121.

    Article  CAS  Google Scholar 

  25. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511: 421–427.

    Article  Google Scholar 

  26. Shi Y, Li Z, Xu Q, Wang T, Li T, Shen J et al. Common variants on 8p12 and 1q24.2 confer risk of schizophrenia. Nat Genet 2011; 43: 1224–1227.

    Article  CAS  Google Scholar 

  27. Yue WH, Wang HF, Sun LD, Tang FL, Liu ZH, Zhang HX et al. Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nat Genet 2011; 43: 1228–1231.

    Article  CAS  Google Scholar 

  28. Kaalund SS, Newburn EN, Ye T, Tao R, Li C, Deep-Soboslay A et al. Contrasting changes in DRD1 and DRD2 splice variant expression in schizophrenia and affective disorders, and associations with SNPs in postmortem brain. Mol Psychiatry 2013; 19: 1258–1266.

    Article  Google Scholar 

  29. Centonze D, Usiello A, Costa C, Picconi B, Erbs E, Bernardi G et al. Chronic haloperidol promotes corticostriatal long-term potentiation by targeting dopamine D2L receptors. J Neurosci 2004; 24: 8214–8222.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Allison Brown and Maura Regan at the HPCGG for coordinating and performing the genotyping for this project, and Sharon Chandler at UCSD and Jessica Lasky-Su at Harvard Medical School for technical assistance. 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. We also 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. We also thank Dr Wolfgang Sadee for generously providing DRD2 minigene constructs. This work was supported in part by grant R01MH085521 (SJG) from the US National Institutes of Health; a Young Investigator Award, an Independent Investigator Award, and the Sidney R Baer, Jr Prize for Schizophrenia Research (SJG) from NARSAD: The Brain and Behavior Research Fund; and a Research Grant from The Gerber Foundation (SJG); as well as the National Health Research Institute of Taiwan (90-8825PP and 91,92-9113PP), National Taiwan University (97R00066-47,48) and the Genomic Medicine Research Program of Psychiatric Disorders of National Taiwan University Hospital, the National Research Program for Genomic Medicine of the National Science Council of Taiwan (NSC-94-3112-B-002; NSC-95-3112-B-002-011; NSC-96-3112-B-002-011; NSC-97-3112-B-002-046), the National Natural Science Foundation of China (30530290, 30870896), the National High Technology Research and Development Program of China (2006AA02Z195, 2008AA02Z401), the National Basic Research Program of China (2007CB512301), the National Health Research Institutes of Zhunan, Taiwan, the National Program 863 (2006AA02A407) of China, the National 973 Program of China (2004CB518601), and the International S&T Cooperation Program of China (2006DFA31440). Cynthia Shannon Weickert is supported by the Schizophrenia Research Institute (utilizing infrastructure funding from the NSW Ministry of Health and the Macquarie Group Foundation), the University of New South Wales, and Neuroscience Research Australia. Cynthia Shannon Weickert is a recipient of a National Health and Medical Research Council (Australia) Senior Research Fellowship.

Author information

Authors and Affiliations

  1. Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, NY, USA

    O S Cohen, J L Hess, L M Paish, S Y McCoy & S J Glatt

  2. School of Psychiatry, University of New South Wales, Randwick, NSW, Australia

    T W Weickert & C S Weickert

  3. Neuroscience Research Australia, Randwick, NSW, Australia

    T W Weickert, D A Rothmond, D D Weinberg & C S Weickert

  4. Schizophrenia Research Institute, Darlinghurst, NSW, Australia

    T W Weickert & C S Weickert

  5. Discipline of Psychiatry, School of Medicine, The University of Adelaide, Adelaide, SA, Australia

    C Galletly

  6. Lyell McEwin Hospital, Salisbury, SA, Australia

    C Galletly, D Liu & X-F Huang

  7. School of Medicine, University of Wollongong and Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia

    X-F Huang

  8. Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China

    Q Xu & Y Shen

  9. Key Laboratory for Mental Health, Ministry of Health, Institute of Mental Health, Peking University, Beijing, China

    D Zhang, W Yue, J Yan, L Wang & T Lu

  10. Bio-X Center, Shanghai Jiao Tong University, Shanghai, China

    L He, Y Shi, M Xu, R Che & W Tang

  11. Division of Mental Health and Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan

    C-H Chen & W-H Chang

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

    H-G Hwu, C-M Liu, Y-L Liu & C-C Wen

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

    H-G Hwu

  14. Neurobiology and Cognitive Science Center, Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan

    H-G Hwu

  15. Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan

    C S-J Fann & C-C Chang

  16. Department of Neuropsychiatry, Ozone Hospital, Osaka Medical College, Osaka, Japan

    T Kanazawa

  17. Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA

    F A Middleton, S V Faraone & S J Glatt

  18. Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA

    T M Duncan

  19. Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA

    S V Faraone & S J Glatt

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

    M T Tsuang

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

    M T Tsuang

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

    M T Tsuang

Authors
  1. O S Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T W Weickert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J L Hess
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L M Paish
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Y McCoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D A Rothmond
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Galletly
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D D Weinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. X-F Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Q Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Y Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. W Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. L Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. T Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. L He
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Y Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. M Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. R Che
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. W Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. C-H Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. W-H Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. H-G Hwu
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. C-M Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Y-L Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. C-C Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. C S-J Fann
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. C-C Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. T Kanazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. F A Middleton
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. T M Duncan
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. S V Faraone
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. C S Weickert
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. M T Tsuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. S J Glatt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S J Glatt.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cohen, O., Weickert, T., Hess, J. et al. A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples. Mol Psychiatry 21, 975–982 (2016). https://doi.org/10.1038/mp.2015.137

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2015.137

This article is cited by

Search

Advanced search

Quick links