title: Analysis of coding-polymorphisms in NOTCH-related genes reveals NUMBL poly-glutamine repeat to be associated with schizophrenia in Brazilian and Danish subjects.
abstract: Abnormality in neurodevelopment is one of the most robust hypotheses on the etiology of schizophrenia and has found substantial support from brain imaging and genetic studies. Neurodevelopmental processes involve several signaling pathways, including the Notch, but little is known at present regarding their possible involvement in schizophrenia. In the present study we investigated the link of non-synonymous variants of five genes of the Notch pathway (NOTCH2, NOTCH3, JAGGED2, ASCL1 and NUMBL) to schizophrenia in a group of 200 Brazilian patients and 200-paired controls. Also, we replicated the association of the NUMBL variant, our most promising finding, in an unrelated set of 684 Danish patients and controls. When the Brazilian and Danish cohorts were merged, a total of 1084 subjects, we found the allele 18 CAG of NUMBL (p=0.003, x2=8.88, OR=1.30, 95% CI 1.09-1.56) as well as the 18/18 CAG genotype (p=0.002, x2=9.46, OR=1.46, 95% CI 1.15-1.87) to be associated with schizophrenia. The consistency of this finding in two independent and unrelated populations reinforces the veracity of this association.
authors.affiliation: Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, Brazil, and University Department of Psychiatry, H:S Frederiksberg Hospital, Denmark.
authors.forename: Sheila
authors.initials: S
authors.lastname: Passos Gregorio
authors.forename: Wagner F
authors.initials: WF
authors.lastname: Gattaz
authors.forename: Hildeberto
authors.initials: H
authors.lastname: Tavares
authors.forename: Christian
authors.initials: C
authors.lastname: Kieling
authors.forename: Sally
authors.initials: S
authors.lastname: Timm
authors.forename: August G
authors.initials: AG
authors.lastname: Wang
authors.forename: Henrik
authors.initials: H
authors.lastname: Berg Rasmussen
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Dias-Neto
mesh_terms: D000328:Adult; D001938:Brazil / Q000453:epidemiology; D017931:DNA Primers / Q000235:genetics; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000072101:Jagged-2 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics*; D012559:Schizophrenia / Q000208:ethnology* / Q000235:genetics*
chemical_list: D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; C490504:JAG2 protein, human; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D051880:Receptors, Notch