Whitton Laura, Cosgrove Donna, Clarkson Christopher, Harold Denise, Kendall Kimberley, Richards Alex, Mantripragada Kiran, Owen Michael J, O'Donovan Michael C, Walters James, Hartmann Annette, Konte Betina, Rujescu Dan, Gill Michael, Corvin Aiden, Rea Stephen, Donohoe Gary, Morris Derek W
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.
Centre for Chromosome Biology, Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.
Am J Med Genet B Neuropsychiatr Genet. 2016 Dec;171(8):1170-1179. doi: 10.1002/ajmg.b.32503. Epub 2016 Oct 20.
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.
表观遗传机制是调控包括基因表达在内的各种基因组功能的重要可遗传且动态的手段，以协调大脑发育、成体神经发生和突触可塑性。这些过程受到干扰时被认为会导致精神分裂症的病理生理。精神分裂症的一个核心特征是认知功能障碍。对于认知障碍更严重的遗传性疾病，如智力残疾，参与基因转录表观遗传调控的基因数量不成比例地高。现在有证据支持精神分裂症和智力残疾之间存在一些共同的遗传病因。全基因组关联研究（GWAS）已经确定了108个与精神分裂症风险相关的染色体区域，涵盖350个基因。本研究确定了映射到那些具有表观遗传功能位点的基因，并测试了定义这些位点的风险等位基因与认知缺陷的关联。我们列出了一份具有表观遗传功能的350个基因的清单，并将其与GWAS位点进行交叉对照。这确定了八个候选基因：BCL11B、CHD7、EP300、EPC2、GATAD2A、KDM3B、RERE、SATB2。使用爱尔兰精神病病例和对照的数据集（n = 1235），测试了这些位点的精神分裂症风险单核苷酸多态性（SNP）对智商、工作记忆、情景记忆和注意力的影响。最强的关联是rs6984242与智商测量值（P = 0.001）和情景记忆（P = 0.007）。我们通过一个远距离表达数量性状基因座（eQTL）将rs6984242与CHD7联系起来。这些关联在独立样本中未得到重复验证。我们的研究强调，许多映射到精神分裂症风险位点的基因可能作为基因表达的表观遗传调节因子发挥作用，但需要进一步研究来确定这些基因在认知中的作用。© 2016威利期刊公司
