Disruption of an epigenetic locus controlling EAAC1 expression in schizophrenia

精神分裂症中控制 EAAC1 表达的表观遗传位点的破坏

• 批准号: 8432795
• 负责人: MARINA MYLES-WORSLEY
• 金额: $ 11.48万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-23 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8432795
• 关键词: 9p24; Address; Adult; Affect; Age-Years; Architecture; Back; Biological Markers; Bipolar Disorder; Candidate Disease Gene; Chromosomes; Clinical assessments; Consent; Control Groups; Control Locus; DNA; DSM-IV; Data Collection; Development; Diagnostic; Disease; Early Intervention; Enrollment; Epigenetic Process; European; Event; Excitatory Amino Acids; Family; Family member; Functional disorder; Funding; Future; Gene Expression; Generations; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genome Scan; Genotype; Glutamate Transporter; Glutamates; Goals; Histones; Individual; Interneurons; Lead; Medical Records; Mental Depression; Methylation; Molecular Genetics; N-Methylaspartate; National Institute of Mental Health; Onset of illness; Outcome; Palau; Phase; Play; Population; Prefrontal Cortex; Prevention; Preventive Intervention; Psychiatric therapeutic procedure; Psychotic Disorders; RNA; Research; Resources; Risk; Role; Sampling; Schizophrenia; Siblings; Site; Spouses; Staging; Symptoms; Synapses; Testing; Update; Variant; Work; adolescent offspring; affection; aspartate receptor; clinical phenotype; density; drug development; epigenetic marker; ethnic difference; excitotoxicity; family genetics; functional disability; functional genomics; gamma-Aminobutyric Acid; gene discovery; genetic pedigree; high risk; improved; interest; intervention program; member; neuropsychiatry; neurotransmission; novel diagnostics; offspring; prevent; research and development; segregation; transmission process

DESCRIPTION (provided by applicant): Our ongoing 20-year family-genetic study of schizophrenia and other psychotic disorders (SCZ) in the isolated population of Palau provides a valuable resource for examining the genetic and epigenetic mechanisms that govern familial transmission of SCZ. We have identified a highly promising copy number variant (CNV) that points to the possible discovery of another "Disrupted-In-Schizophrenia" locus. This structural variant clearly co-segregates with SCZ in a 5- generation, high-density Palauan family. Genetic, epigenetic, and functional genomic lines of evidence support its relevance for SCZ. The deletion occurs at a 9p24 site that controls histone methylation, an important epigenetic event in glutamatergic gene expression. This epigenetic locus is adjacent to the EAAC1 (excitatory-amino-acid-carrier-1) glutamate transporter gene, which plays an essential role in regulating glutamatergic neurotransmission, a well- recognized component of the pathophysiology of SCZ. The Palauan family with the 9p24 deletion is as large and as densely affected as the Scottish family that led to the discovery of the original DISC1 gene. Our preliminary studies have validated the deletion status in all affected and unaffected family members, and indicated that EAAC1 gene expression is reduced in SCZ family members with the deletion. The goals of the present application are to expand our phenotypic and genotypic assessments to include all members of the extended pedigree (N = ~75), test for co-segregation of the deletion with affection status, and conduct preliminary studies to examine the possible functional significance of the deletion in terms of EAAC1 gene expression and histone methylation levels at the 9p24 locus. Once completed, the study will provide "proof of concept" for a full-scale R01 study of the functional consequences of this disruption and its potential as a diagnostic biomarker for SCZ and possible target for drug development. Ultimately, this line of research may lead to improved risk prediction and treatment decisions for young high-risk individuals in the prodromal stage of SCZ when preventive intervention can be most effective.

描述（由申请人提供）：我们在帕劳孤立人群中对精神分裂症和其他精神疾病（SCZ）进行了20年的家族遗传研究，为研究控制SCZ家族传播的遗传和表观遗传机制提供了宝贵的资源。我们已经确定了一个非常有希望的拷贝数变异（CNV），指出可能发现另一个“精神分裂症中的紊乱”位点。在一个5代高密度的帕劳家族中，这种结构变异明显与SCZ共分离。遗传学、表观遗传学和功能基因组线的证据支持其与SCZ的相关性。这种缺失发生在控制组蛋白甲基化的9p24位点，这是谷氨酸能基因表达中的一个重要表观遗传事件。这个表观遗传位点与EAAC1（兴奋性氨基酸载体-1）谷氨酸转运蛋白基因相邻，该基因在调节谷氨酸能神经传递中起重要作用，这是SCZ病理生理的一个公认的组成部分。9p24缺失的帕劳家族与发现原始DISC1基因的苏格兰家族一样庞大，受影响程度也一样高。我们的初步研究验证了所有受影响和未受影响的家族成员的缺失状态，并表明EAAC1基因在SCZ家族成员中表达减少。本申请的目标是扩大我们的表型和基因型评估，包括扩展谱系的所有成员（N = ~75），检测缺失与情感状态的共分离，并进行初步研究，以检查缺失在9p24位点EAAC1基因表达和组蛋白甲基化水平方面可能的功能意义。一旦完成，该研究将为全面的R01研究提供“概念证明”，以研究这种破坏的功能后果，以及它作为SCZ诊断生物标志物和可能的药物开发靶点的潜力。最终，这条研究路线可能会导致在预防性干预最有效的SCZ前驱期的年轻高危个体的风险预测和治疗决策的改进。