Disruption of an epigenetic locus controlling EAAC1 expression in schizophrenia

描述(申请人提供)：我们在帕劳与世隔绝的人群中对精神分裂症和其他精神障碍(SCZ)进行了长达20年的家族遗传学研究，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体(CNV)，它表明可能发现了另一个“精神分裂症中断”基因座。这种结构变异明显地与SCZ共同隔离在一个5代高密度的帕劳家庭中。遗传的、表观遗传的和功能基因组的证据支持它与SCZ的相关性。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的一个重要表观遗传事件。该表观遗传位点与谷氨酸转运体基因EAAC1相邻，EAAC1基因在调节谷氨酸能神经传递中起重要作用，谷氨酸能神经传递是SCZ病理生理的重要组成部分。缺失9p24的帕劳家庭与导致发现原始DISC1基因的苏格兰家庭一样大，也一样受影响。我们的初步研究已经证实了所有受影响和未受影响的家庭成员的EAAC1基因缺失状态，并表明有缺失的SCZ家族成员EAAC1基因表达降低。本申请的目的是扩大我们的表型和基因分型评估，以包括扩大的家系中的所有成员(N=~75)，测试缺失与情感状态的共分离，并进行初步研究，根据EAAC1基因表达和9p24基因座上的组蛋白甲基化水平来检验缺失可能的功能意义。一旦完成，这项研究将为这种干扰的功能后果及其作为SCZ的诊断生物标记物和药物开发的可能目标的全面R01研究提供“概念证明”。最终，这一研究路线可能会改善预防干预最有效的SCZ前驱阶段年轻高危个体的风险预测和治疗决策。 公共卫生相关性：我们建议的研究直接涉及旨在预防和治疗最令人衰弱的神经精神疾病：精神分裂症、抑郁症和双相情感障碍的研究需要。利用一个非同寻常的6代SCZ家族，我们的目标是在年轻人中识别精神病障碍的风险预测因素，这些年轻人在进入成年后对疾病发展具有强烈的遗传易感性。这项拟议的发育性研究代表着朝着下一代诊断和治疗迈出的一步，这些诊断和治疗旨在识别处于早期前驱阶段的新出现的精神病，此时预防性干预可以最有效。由于发病后治疗对病程和结果的影响有限，精神障碍的前驱阶段是早期干预的重要机会之窗。针对有前驱症状的年轻人的预防性干预计划已被证明可以推迟甚至预防疾病的发生，并降低与精神障碍相关的致残性功能残疾的风险。

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. PUBLIC HEALTH RELEVANCE: Our proposed study directly addresses the need for research aimed at the prevention and treatment of the most debilitating neuropsychiatric disorders: schizophrenia, depression and bipolar disorder. Using an extraordinary 6-generation SCZ family, we aim to identify risk predictors for psychotic disorders in young people who carry a strong genetic susceptibility for disease development as they enter their adult years. The proposed developmental study represents a step toward the next generation of diagnostics and treatments that aim to identify emerging psychosis in its early prodromal stage when preventive intervention can be most effective. Because post-onset treatment has limited impact on course and outcome, the prodromal phase of psychotic disorders represent an important window of opportunity for early intervention. Preventive intervention programs for young people with prodromal symptoms have been shown to delay or even prevent illness onset and reduce the risk of the crippling functional disabilities associated with psychotic disorders.