title: Investigation of SHANK3 in schizophrenia.
abstract: The postsynaptic scaffolding protein SHANK3 is essential for the normal function of glutamatergic synapses in the brain. Emerging evidence suggests that impaired plasticity of glutamatergic synapses contributes to the pathology of schizophrenia (SCZ). To investigate whether variants in the SHANK3 gene contribute to the etiology of SCZ, we sequenced SHANK3 in 500 affected individuals (cohort C1). In total, we identified 48 variants and compared them to European controls from the 1000 Genomes Project and the Exome Variant Server. Five variants showed significant differences in frequencies between patients and controls. We were able to follow three of them up in an independent cohort (C2) comprising 993 SCZ patients and 932 German controls. We could not confirm an association for three of these variants (rs140201628, rs1557620, and rs61729471). Two rare variants with predicted functional relevance were identified in further SCZ individuals of cohort C1: c.3032G>T (p.G1011V) and c.*27C>T. The latter variant was found in one additional SCZ individual and the p.G1011V variant was identified in two additional SCZ individuals from cohort C2. The p.G1011V variant was the most interesting variant in our study; together with previous studies this variant has been identified in 4 out of 1,524 SCZ patients and in 4 out of 2,147 individuals with autism spectrum disorder (ASD), but not in 2468 European Sanger-sequenced controls. Therefore, we consider this variant a promising candidate variant for follow-up studies in larger samples and functional investigations. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: de Sena Cortabitarte
authors.affiliation: Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.|Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Degenhardt
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health Mannheim, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Strohmaier
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health Mannheim, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Lang
authors.affiliation: Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Weiss
authors.affiliation: Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Roeth
authors.affiliation: Department of Psychiatry, University Hospital Halle (Saale), Halle, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.affiliation: Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heilmann-Heimbach
authors.affiliation: Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hofmann
authors.affiliation: Department of Psychiatry, University Hospital Halle (Saale), Halle, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Fischer
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health Mannheim, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.|Department of Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.|Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.|Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Heidelberg, Germany.
authors.forename: Gudrun A
authors.initials: GA
authors.lastname: Rappold
authors.affiliation: Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Berkel
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D059472:Exome / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011379:Prognosis; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology
chemical_list: D009419:Nerve Tissue Proteins; C492357:SHANK3 protein, human
keywords: SHANK; autism; intellectual disability; schizophrenia