A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples
Journal
Molecular Psychiatry
Journal Volume
21
Journal Issue
7
Pages
975-982
Date Issued
2016
Author(s)
Cohen O.S.
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.-H.
Chang W.-H.
Liu Y.-L.
Wen C.-C.
Fann C.S.-J.
Chang C.-C.
Kanazawa T.
Middleton F.A.
Duncan T.M.
Faraone S.V.
Weickert C.S.
Tsuang M.T.
Glatt S.J.
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. ? 2016 Macmillan Publishers Limited.
Other Subjects
chlorpromazine; DNA; dopamine 2 receptor; haloperidol; messenger RNA precursor; olanzapine; RNA isoform; unclassified drug; zinc finger protein; Zinc Finger RAN Binding Domain Containing 2; dopamine 2 receptor; DRD2 protein, human; RNA binding protein; RNA precursor; ZRANB2 protein, human; adult; allele; alternative RNA splicing; animal experiment; animal model; animal tissue; Article; association rate constant; autopsy; binding affinity; binding site; brain weight; cognitive defect; comprehension; controlled study; disease predisposition; dissociation; DNA polymorphism; drug exposure; exon; female; gene disruption; gene expression; gene frequency; gene replication; genetic association; genetic model; genetic risk; genetic susceptibility; genetic transfection; genotype; Han Chinese; heterozygote; homozygote; human; human tissue; learning; major clinical study; male; molecular pathology; nonhuman; observed rate constant; oligonucleotide probe; population based case control study; priority journal; protein binding; psychopharmacotherapy; rat; schizophrenia; task performance; verbal comprehension; verbal fluency; working memory; alternative RNA splicing; brain; China; cognition; ethnic group; genetic predisposition; genetics; metabolism; physiology; risk factor; RNA splicing; schizophrenia; single nucleotide polymorphism; Adult; Alleles; Alternative Splicing; Brain; China; Cognition; Ethnic Groups; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Polymorphism, Single Nucleotide; Receptors, Dopamine D2; Risk Factors; RNA Precursors; RNA Splicing; RNA-Binding Proteins; Schizophrenia
Type
journal article