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


O S. Cohen, SUNY Upstate Medical University
T W. Weickert, Schizophrenia Research Institute, SydneyFollow
J L. Hess, SUNY Upstate Medical University
L M. Paish, SUNY Upstate Medical University
S Y. Mccoy, SUNY Upstate Medical University
D A. Rothmond, Prince of Wales Medical Research Institute
Cherrie Galletly, University of Adelaide
D Liu, Lyell McEwin Hospital
D D. Weinberg, Neuroscience Research Australia
Xu-Feng Huang, University of WollongongFollow
Q Xu, Chinese Academy of Medical Sciences
Y Shen, Chinese Academy of Medical Sciences
D Zhang, Peking University
W Yue, Peking University
J Yan, Peking University
L F. Wang, Peking Union Medical College
T Lu, Peking University
Lin He, Shanghai Jiao Tong University
Yishan Shi, Shanghai Jiao Tong University
M Xu, Shanghai Jiao Tong University
Ronglin Che, Shanghai Jiao Tong University
Wei Tang, Shanghai Jiao Tong University
C-H Chen, National Health Research Institutes
W-H Chang, National Health Research Institutes
H-G Hwu, National Taiwan University
C-M Liu, National Taiwan University
Y-L Liu, National Taiwan University
C-C Wen, National Taiwan University
Cs-J Fann, Institute of Biomedical Science
C-C Chang, Institute of Biomedical Science
T Kanazawa, Osaka Medical College
F A. Middleton, SUNY Upstate Medical University
T M. Duncan, SUNY Upstate Medical University
S V. Faraone, SUNY Upstate Medical University
Cynthia Shannon Weickert, University of New South Wales
M T. Tsuang, University of California, San Diego
S Glatt, SUNY Upstate Medical University



Publication Details

Cohen, O., Weickert, T. W., Hess, J. L., Paish, L. M., Mccoy, S. Y., Rothmond, D. A., Galletly, C., Liu, D., Weinberg, D. D., Huang, X. F., Xu, Q., Shen, Y., Zhang, D.,Yue, W., Yan, J., Wang, L., Lu, T., He, L., Shi, Y., Xu, M., Che, R., Tang, W., Chen, C., Chang, W., Hwu, H., Liu, C., Liu, Y., Wen, C., Fann, C., Chang, C., Kanazawa, T.,Middleton, F. A., Duncan, T. M., Faraone, S. V., Weickert, C. S., Tsuang, M. T. & Glatt, S. J. (2016). A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples. Molecular Psychiatry, 21 975-982.


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.

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