title: Combined analysis of exon splicing and genome wide polymorphism data predict schizophrenia risk loci.
abstract: Schizophrenia has a strong genetic basis, and genome-wide association studies (GWAS) have shown that effect sizes for individual genetic variants which increase disease risk are small, making detection and validation of true disease-associated risk variants extremely challenging. Specifically, we first identify genes with exons showing differential expression between cases and controls, indicating a splicing mechanism that may contribute to variation in disease risk and focus on those showing consistent differential expression between blood and brain tissue. We then perform a genome-wide screen for SNPs associated with both normalised exon intensity of these genes (so called splicing QTLs) as well as association with schizophrenia. We identified a number of significantly associated loci with a biologically plausible role in schizophrenia, including MCPH1, DLG3, ZC3H13, and BICD2, and additional loci that influence splicing of these genes, including YWHAH. Our approach of integrating genome-wide exon intensity with genome-wide polymorphism data has identified a number of plausible SZ associated loci.
authors: Hunter Medical Research Institute and Faculty of Health, University of Newcastle, NSW, Australia. Electronic address: christopher.oldmeadow@newcastle.edu.au.
authors: Christopher
authors: C
authors: Oldmeadow
authors: Hunter Medical Research Institute and Faculty of Health, University of Newcastle, NSW, Australia; School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, NSW, Australia; Schizophrenia Research Institute, Sydney, NSW, Australia.
authors: David
authors: D
authors: Mossman
authors: Hunter Medical Research Institute and Faculty of Health, University of Newcastle, NSW, Australia.
authors: Tiffany-Jane
authors: TJ
authors: Evans
authors: Hunter Medical Research Institute and Faculty of Health, University of Newcastle, NSW, Australia.
authors: Elizabeth G
authors: EG
authors: Holliday
authors: School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, NSW, Australia; Schizophrenia Research Institute, Sydney, NSW, Australia.
authors: Paul A
authors: PA
authors: Tooney
authors: School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, NSW, Australia; Schizophrenia Research Institute, Sydney, NSW, Australia.
authors: Murray J
authors: MJ
authors: Cairns
authors: School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, NSW, Australia; Schizophrenia Research Institute, Sydney, NSW, Australia.
authors: Jingqin
authors: J
authors: Wu
authors: Schizophrenia Research Institute, Sydney, NSW, Australia; Research Unit for Schizophrenia Epidemiology, School of Psychiatry, University of New South Wales, Australia.
authors: Vaughan
authors: V
authors: Carr
authors: Hunter Medical Research Institute and Faculty of Health, University of Newcastle, NSW, Australia.
authors: John R
authors: JR
authors: Attia
authors: Hunter Medical Research Institute and Faculty of Health, University of Newcastle, NSW, Australia; School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, NSW, Australia; Division of Molecular Medicine, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia.
authors: Rodney J
authors: RJ
authors: Scott
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics; D000704:Analysis of Variance; D001921:Brain / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics; D003598:Cytoskeletal Proteins; D005091:Exons / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D016601:RNA-Binding Proteins; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics
chemical_list: D048948:14-3-3 Proteins; C561542:BICD2 protein, human; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C116869:DLG3 protein, human; C460645:MCPH1 protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C482984:YWHAH protein, human; C556840:ZC3H13 protein, human
keywords: Alternative splicing; Exons; GWAS; Genetics; Phosphorylation; Schizophrenia