title: Cognitive analysis of schizophrenia risk genes that function as epigenetic regulators of gene expression.
abstract: Epigenetic mechanisms are an important heritable and dynamic means of regulating various genomic functions, including gene expression, to orchestrate brain development, adult neurogenesis, and synaptic plasticity. These processes when perturbed are thought to contribute to schizophrenia pathophysiology. A core feature of schizophrenia is cognitive dysfunction. For genetic disorders where cognitive impairment is more severe such as intellectual disability, there are a disproportionally high number of genes involved in the epigenetic regulation of gene transcription. Evidence now supports some shared genetic aetiology between schizophrenia and intellectual disability. GWAS have identified 108 chromosomal regions associated with schizophrenia risk that span 350 genes. This study identified genes mapping to those loci that have epigenetic functions, and tested the risk alleles defining those loci for association with cognitive deficits. We developed a list of 350 genes with epigenetic functions and cross-referenced this with the GWAS loci. This identified eight candidate genes: BCL11B, CHD7, EP300, EPC2, GATAD2A, KDM3B, RERE, SATB2. Using a dataset of Irish psychosis cases and controls (n = 1235), the schizophrenia risk SNPs at these loci were tested for effects on IQ, working memory, episodic memory, and attention. Strongest associations were for rs6984242 with both measures of IQ (P = 0.001) and episodic memory (P = 0.007). We link rs6984242 to CHD7 via a long range eQTL. These associations were not replicated in independent samples. Our study highlights that a number of genes mapping to risk loci for schizophrenia may function as epigenetic regulators of gene expression but further studies are required to establish a role for these genes in cognition. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition and Genomics (NICOG) Centre and NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.
authors.forename: Laura
authors.initials: L
authors.lastname: Whitton
authors.affiliation: Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition and Genomics (NICOG) Centre and NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.
authors.forename: Donna
authors.initials: D
authors.lastname: Cosgrove
authors.affiliation: Centre for Chromosome Biology, Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.
authors.forename: Christopher
authors.initials: C
authors.lastname: Clarkson
authors.affiliation: Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine and Discipline of Psychiatry, Trinity College Dublin, Dublin, Ireland.|School of Biotechnology, Dublin City University, Dublin, Ireland.
authors.forename: Denise
authors.initials: D
authors.lastname: Harold
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Kendall
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Alex
authors.initials: A
authors.lastname: Richards
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Kiran
authors.initials: K
authors.lastname: Mantripragada
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Walters
authors.affiliation: Department of Psychiatry, University of Halle, Halle, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Department of Psychiatry, University of Halle, Halle, Germany.
authors.forename: Betina
authors.initials: B
authors.lastname: Konte
authors.affiliation: Department of Psychiatry, University of Halle, Halle, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine and Discipline of Psychiatry, Trinity College Dublin, Dublin, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.affiliation: Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine and Discipline of Psychiatry, Trinity College Dublin, Dublin, Ireland.
authors.forename: Aiden
authors.initials: A
authors.lastname: Corvin
authors.affiliation: Centre for Chromosome Biology, Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.
authors.forename: Stephen
authors.initials: S
authors.lastname: Rea
authors.affiliation: Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition and Genomics (NICOG) Centre and NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.
authors.forename: Gary
authors.initials: G
authors.lastname: Donohoe
authors.affiliation: Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition and Genomics (NICOG) Centre and NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.
authors.forename: Derek W
authors.initials: DW
authors.lastname: Morris
mesh_terms: D000328:Adult; D000483:Alleles; D001921:Brain / Q000378:metabolism; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000235:genetics* / Q000523:psychology; D044127:Epigenesis, Genetic / Q000235:genetics*; D057890:Epigenomics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007494:Ireland; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011618:Psychotic Disorders / Q000235:genetics; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*; D012565:Schizophrenic Psychology
keywords: GWAS; cognition; epigenetics; gene; schizophrenia