title: Investigation of the role of TCF4 rare sequence variants in schizophrenia.
abstract: Transcription factor 4 (TCF4) is one of the most robust of all reported schizophrenia risk loci and is supported by several genetic and functional lines of evidence. While numerous studies have implicated common genetic variation at TCF4 in schizophrenia risk, the role of rare, small-sized variants at this locus-such as single nucleotide variants and short indels which are below the resolution of chip-based arrays requires further exploration. The aim of the present study was to investigate the association between rare TCF4 sequence variants and schizophrenia. Exon-targeted resequencing was performed in 190 German schizophrenia patients. Six rare variants at the coding exons and flanking sequences of the TCF4 gene were identified, including two missense variants and one splice site variant. These six variants were then pooled with nine additional rare variants identified in 379 European participants of the 1000 Genomes Project, and all 15 variants were genotyped in an independent German sample (n = 1,808 patients; n = 2,261 controls). These data were then analyzed using six statistical methods developed for the association analysis of rare variants. No significant association (P < 0.05) was found. However, the results from our association and power analyses suggest that further research into the possible involvement of rare TCF4 sequence variants in schizophrenia risk is warranted by the assessment of larger cohorts with higher statistical power to identify rare variant associations.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, Bonn, Germany.
authors.forename: F Buket
authors.initials: FB
authors.lastname: Basmanav
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, Bonn, Germany.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Forstner
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, Bonn, Germany.|Department of Genomic Mathematics, University of Bonn, Bonn, Germany.
authors.forename: Heide
authors.initials: H
authors.lastname: Fier
authors.affiliation: Department of Genomics, Life and Brain Center, Bonn, Germany.|Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Herms
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.|National Center for Register-Based Research, Aarhus University, Aarhus, Denmark.
authors.forename: Sandra
authors.initials: S
authors.lastname: Meier
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, Bonn, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Degenhardt
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, Bonn, Germany.|Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.|Institute of Neuroscience and Medicine INM-1, Research Center Juelich, Juelich, Germany.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, Bonn, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Barth
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, Bonn, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Fricker
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Strohmaier
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Schmael
authors.affiliation: Centre of Urban Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Essen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Moebus
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.|Department of Psychiatry, University of Tübingen.
authors.forename: Rainald
authors.initials: R
authors.lastname: Mössner
authors.affiliation: Department of Psychiatry, University of Halle, Halle, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Department of Genomic Mathematics, University of Bonn, Bonn, Germany.|German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, Bonn, Germany.|Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.|Institute of Neuroscience and Medicine INM-1, Research Center Juelich, Juelich, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D012559:Schizophrenia / Q000235:genetics*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors
keywords: neurodevelopmental disorder; rare variants; resequencing; schizophrenia; transcription factor 4