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

基本信息

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
项目类别：
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

项目摘要

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）：我们对帕劳孤立人群中的精神分裂症和其他精神病 (SCZ) 正在进行 20 年的家族遗传学研究，为检查控制 SCZ 家族传播的遗传和表观遗传机制提供了宝贵的资源。我们已经发现了一个非常有前途的拷贝数变异（CNV），它表明可能发现另一个“精神分裂症中断”基因座。这种结构变异明显与 SCZ 在 5 代高密度帕劳家族中共分离。遗传、表观遗传和功能基因组证据支持其与 SCZ 的相关性。该缺失发生在控制组蛋白甲基化的 9p24 位点，组蛋白甲基化是谷氨酸能基因表达中重要的表观遗传事件。该表观遗传位点与 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发挥着重要作用，而谷氨酸神经传递是 SCZ 病理生理学中公认的组成部分。具有 9p24 缺失的帕劳家族与导致原始 DISC1 基因发现的苏格兰家族一样庞大且受到影响。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 SCZ 家族成员中 EAAC1 基因表达随着缺失而降低。本申请的目标是扩大我们的表型和基因型评估，以包括扩展谱系的所有成员（N = ~75），测试删除与情感状态的共分离，并进行初步研究以检查可能的功能9p24 位点上 EAAC1 基因表达和组蛋白甲基化水平的缺失的意义。一旦完成，该研究将为全面的 R01 研究提供“概念证明”，研究这种破坏的功能后果及其作为 SCZ 诊断生物标志物和药物开发可能目标的潜力。最终，这一系列研究可能会改善 SCZ 前驱阶段年轻高危个体的风险预测和治疗决策，此时预防性干预最为有效。