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A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples
- Source :
- Molecular Psychiatry. 21:975-982
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
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.
- Subjects :
- Adult
Male
0301 basic medicine
China
medicine.medical_specialty
Genotype
RNA Splicing
Polymorphism, Single Nucleotide
03 medical and health sciences
Cellular and Molecular Neuroscience
Splicing factor
Cognition
0302 clinical medicine
Risk Factors
Internal medicine
Dopamine receptor D2
Ethnicity
RNA Precursors
medicine
Humans
Verbal fluency test
Genetic Predisposition to Disease
Receptor
Molecular Biology
Alleles
Receptors, Dopamine D2
Alternative splicing
Brain
RNA-Binding Proteins
Odds ratio
Alternative Splicing
Psychiatry and Mental health
030104 developmental biology
Endocrinology
RNA splicing
Schizophrenia
Female
Psychopharmacology
Psychology
030217 neurology & neurosurgery
Clinical psychology
Subjects
Details
- ISSN :
- 14765578 and 13594184
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Molecular Psychiatry
- Accession number :
- edsair.doi.dedup.....00c8f2be3e1803af3f9f2f26542db07c