A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples.
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.
Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, NY, USA.
O S
OS
Cohen
School of Psychiatry, University of New South Wales, Randwick, NSW, Australia.|Neuroscience Research Australia, Randwick, NSW, Australia.|Schizophrenia Research Institute, Darlinghurst, NSW, Australia.
T W
TW
Weickert
Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, NY, USA.
J L
JL
Hess
Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, NY, USA.
L M
LM
Paish
Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, NY, USA.
S Y
SY
McCoy
Neuroscience Research Australia, Randwick, NSW, Australia.
D A
DA
Rothmond
Discipline of Psychiatry, School of Medicine, The University of Adelaide, Adelaide, SA, Australia.|Lyell McEwin Hospital, Salisbury, SA, Australia.
C
C
Galletly
Lyell McEwin Hospital, Salisbury, SA, Australia.
D
D
Liu
Neuroscience Research Australia, Randwick, NSW, Australia.
D D
DD
Weinberg
Lyell McEwin Hospital, Salisbury, SA, Australia.|School of Medicine, University of Wollongong and Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.
X-F
XF
Huang
Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
Q
Q
Xu
Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
Y
Y
Shen
Key Laboratory for Mental Health, Ministry of Health, Institute of Mental Health, Peking University, Beijing, China.
D
D
Zhang
Key Laboratory for Mental Health, Ministry of Health, Institute of Mental Health, Peking University, Beijing, China.
W
W
Yue
Key Laboratory for Mental Health, Ministry of Health, Institute of Mental Health, Peking University, Beijing, China.
J
J
Yan
Key Laboratory for Mental Health, Ministry of Health, Institute of Mental Health, Peking University, Beijing, China.
L
L
Wang
Key Laboratory for Mental Health, Ministry of Health, Institute of Mental Health, Peking University, Beijing, China.
T
T
Lu
Bio-X Center, Shanghai Jiao Tong University, Shanghai, China.
L
L
He
Bio-X Center, Shanghai Jiao Tong University, Shanghai, China.
Y
Y
Shi
Bio-X Center, Shanghai Jiao Tong University, Shanghai, China.
M
M
Xu
Bio-X Center, Shanghai Jiao Tong University, Shanghai, China.
R
R
Che
Bio-X Center, Shanghai Jiao Tong University, Shanghai, China.
W
W
Tang
Division of Mental Health and Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.
C-H
CH
Chen
Division of Mental Health and Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.
W-H
WH
Chang
Department of Psychiatry, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Psychology, College of Science, National Taiwan University, Taipei, Taiwan.|Neurobiology and Cognitive Science Center, Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan.
H-G
HG
Hwu
Department of Psychiatry, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
C-M
CM
Liu
Department of Psychiatry, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
Y-L
YL
Liu
Department of Psychiatry, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
C-C
CC
Wen
Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan.
C S-J
CS
Fann
Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan.
C-C
CC
Chang
Department of Neuropsychiatry, Ozone Hospital, Osaka Medical College, Osaka, Japan.
T
T
Kanazawa
Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
F A
FA
Middleton
Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA.
T M
TM
Duncan
Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.|Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
S V
SV
Faraone
School of Psychiatry, University of New South Wales, Randwick, NSW, Australia.|Neuroscience Research Australia, Randwick, NSW, Australia.|Schizophrenia Research Institute, Darlinghurst, NSW, Australia.
C S
CS
Weickert
Department of Psychiatry, Center for Behavioral Genomics, University of California, San Diego, La Jolla, CA, USA.|Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard Departments of Epidemiology and Psychiatry, Boston, MA, USA.|Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
M T
MT
Tsuang
Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, NY, USA.|Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.|Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
S J
SJ
Glatt
D000328:Adult; D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics; D001921:Brain / Q000378:metabolism; D002681:China; D003071:Cognition / Q000502:physiology; D005006:Ethnicity / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012322:RNA Precursors / Q000378:metabolism; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism
C581293:DRD2 protein, human; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D017448:Receptors, Dopamine D2; C486373:ZRANB2 protein, human