Disruption of an epigenetic locus controlling EAAC1 expression in schizophrenia

描述（由申请人提供）：我们正在进行的为期20年的帕劳隔离人群中精神分裂症和其他精神病性障碍（SCZ）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“分裂症”基因座。这种结构变异明显共分离与SCZ在5代，高密度帕劳家庭。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9 p24位点，这是一个重要的表观遗传事件，在肿瘤基因表达中。该表观遗传基因座与EAAC 1（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（SCZ病理生理学的公认组分）中起重要作用。9 p24缺失的帕劳家族与导致发现原始DISC 1基因的苏格兰家族一样大，受影响程度也一样高。我们的初步研究已经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EAAC 1基因表达在SCZ家族成员中的缺失降低。本申请的目标是扩展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），测试缺失与情感状态的共分离，并进行初步研究以检查缺失在9 p24基因座处的EAAC 1基因表达和组蛋白甲基化水平方面的可能的功能意义。一旦完成，该研究将为全面的R 01研究提供“概念验证”，该研究将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靶点的潜力。最终，这一系列的研究可能会导致改善风险预测和治疗决策的年轻高风险的个人在前驱阶段的SCZ时，预防性干预可以是最有效的。

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.