title: GSK3B polymorphisms alter transcription and splicing in Parkinson's disease.
abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by a combination of motor symptoms. We identified two functional single nucleotide polymorphisms in the glycogen synthase kinase-3beta gene (GSK3B). A promoter single nucleotide polymorphism (rs334558) is associated with transcriptional strength in vitro in which the T allele has greater activity. An intronic single nucleotide polymorphism (rs6438552) regulates selection of splice acceptor sites in vitro. The T allele is associated with altered splicing in lymphocytes and increased levels of GSK3B transcripts that lack exons 9 and 11 (GSKDeltaexon9+11). Increased levels of GSKDeltaexon9+11 correlated with enhanced phosphorylation of its substrate, Tau. In a comparison of PD and control brains, there was increased in frequency of T allele (rs6438552) and corresponding increase in GSKDeltaexon9+11 and Tau phosphorylation in PD brains. Conditional logistic regression indicated gene-gene interaction between T/T genotype of rs334558 and H1/H1 haplotype of microtubule-associated protein Tau (MAPT) gene (p = 0.009). There was association between a haplotype (T alleles of both GSK3B polymorphisms) and disease risk after stratification by Tau haplotypes ((H1/H2+H2/H2 individuals: odds ratio, 1.64; p = 0.007; (H1/H1 individuals: odds ratio, 0.68; p < 0.001). Ours results suggest GSK3B polymorphisms alter transcription and splicing and interact with Tau haplotypes to modify disease risk in PD.
authors.affiliation: Garvan Institute of Medical Research, University of New South Wales, Barker Street, Randwick, Sydney NSW 2031, Australia.
authors.forename: John B J
authors.initials: JB
authors.lastname: Kwok
authors.forename: Marianne
authors.initials: M
authors.lastname: Hallupp
authors.forename: Clement T
authors.initials: CT
authors.lastname: Loy
authors.forename: Daniel K Y
authors.initials: DK
authors.lastname: Chan
authors.forename: Jean
authors.initials: J
authors.lastname: Woo
authors.forename: George D
authors.initials: GD
authors.lastname: Mellick
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.forename: Peter A
authors.initials: PA
authors.lastname: Silburn
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
authors.forename: Peter R
authors.initials: PR
authors.lastname: Schofield
mesh_terms: D000368:Aged; D001921:Brain / Q000502:physiology; D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008214:Lymphocytes / Q000502:physiology; D008297:Male; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012326:RNA Splicing / Q000502:physiology*; D012307:Risk Factors; D015533:Transcriptional Activation / Q000502:physiology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3