Neurogenomic Investigations of Trichotillomania and Excoriation Disorder

项目摘要/摘要 毛发狂症(拔头发)和咬伤(抓皮肤)障碍使人虚弱，难以治疗 强迫症(OCD)谱系疾病，没有一线药物干预。 以前的工作支持共同的遗传因素在这些以身体为中心的重复性疾病的发展中的作用 行为(BFRb)的研究进展缓慢，但在确定BFRB风险基因和生物途径方面进展缓慢。 本次K08奖项申请的科学目标是使用一系列互补的、不偏不倚的 最先进的神经遗传学方法，以促进我们对潜在的基因和途径的理解 这是朝着开发改进的治疗方法迈出的重要一步。完成本K08建议书 将在几个关键领域为奥尔夫森博士提供关键的新培训，以实现她的长期职业目标 成为神经基因组学领域的独立研究员。我们的中心假设是破坏DNA 与对照组和iSPC脑相比，患有BFRBs的个体的序列和结构变异丰富 有机化合物可以阐明趋同的神经发育机制。以强劲的初步数据为指导 奥尔夫森博士从BFRB亲子三人组的完整外显子DNA测序(WES)中产生了这个假说 将在3个具体目标中进行审查。在目标1中，我们建议扩大我们的BFRB队列，以在200年内进行WES 亲子三人组。我们将(I)比较病例和罕见的遗传性WES突变率 对照三人组，(Ii)使用先前的400检查强迫症谱系中共享的序列变异遗传风险 对强迫症三重奏进行测序，以及(Iii)整合系统分析以确定生物途径、基因网络和 表情模式。在目标2中，奥尔夫森博士将开发新的技能，通过以下方式分析拷贝数变体(CNV) 对BFRB亲子三人组进行首个全基因组CNV研究。我们将(I)比较从头开始和 在BFRB和对照三组中罕见的遗传性CNV负担，(Ii)检查强迫症频谱中的CNV，以及(Iii) 将CNV数据与目标1的结果相结合，用于系统分析中的重现和丰富。在《目标3》中，Dr。 奥尔夫森将扩展她在IPSC脑有机体方面的技能，以评估早期神经发育机制 BFRb。我们将首先对来自4名患者和未受影响的性别匹配的IPSC脑器官进行表征- 通过单细胞RNA测序比较(I)神经分化和(Ii)转录组。 总体而言，这项K08建议不仅将提高我们对BFRB神经生物学的基础知识，而且 也为奥尔夫森博士提供必要的重要培训，以发展独立的神经基因组研究 计划，继续她对BFRBs和其他神经精神疾病的研究。这项培训计划 涉及一个主要设在耶鲁儿童研究中心的多学科指导团队，具有以下专业知识 基因组学(费尔南德斯博士和沙尔夫博士)、iSPC脑有机化合物(瓦卡里诺博士和费尔南德斯博士)，以及 BFRBs(Bloch博士和Scharf博士)。总的来说，这些导师将为奥尔夫森博士提供指导和 以确保她成功地成为翻译神经基因组学领域的独立内科医生兼科学家。

PROJECT SUMMARY/ABSTRACT Trichotillomania (hair pulling) and excoriation (skin picking) disorder are debilitating, difficult-to-treat obsessive-compulsive disorder (OCD) spectrum conditions with no first-line pharmacologic interventions. Previous work supports the role of shared genetic factors in the development of these body-focused repetitive behaviors (BFRBs), but progress in identifying BFRB risk genes and biological pathways has been slow. The scientific objective of this K08 award application is to use a series of complementary, unbiased state-of-art neurogenetic approaches to advance our understanding of the genes and pathways that underly BFRBs, which is an important step towards developing improved treatments. Completion of this K08 proposal will provide Dr. Olfson with critical new training in several key areas to achieve her long-term career goal of becoming an independent investigator in neurogenomics. Our central hypothesis is that damaging DNA sequence and structural variants are enriched in individuals with BFRBs compared to controls, and iSPC brain organoids can shed light on convergent neurodevelopmental mechanisms. Guided by strong preliminary data generated by Dr. Olfson from whole-exome DNA sequencing (WES) in BFRB parent-child trios, this hypothesis will be examined in 3 specific aims. In Aim 1, we propose expanding our BFRB cohort to conduct WES in 200 parent-child trios. We will (i) compare de novo and rare inherited WES mutation rates between case and control trios, (ii) examine shared sequence variant genetic risk across the OCD spectrum using 400 previously sequenced OCD trios, and (iii) integrate systems analyses to identify biologic pathways, gene networks, and expression patterns. In Aim 2, Dr. Olfson will develop new skills in analyzing copy-number variants (CNVs) by conducting the first genome-wide CNV study of BFRB parent-child trios. We will (i) compare the de novo and rare inherited CNV burden in the BFRB and control trios, (ii) examine CNVs across the OCD spectrum, and (iii) integrate CNV data with results from Aim 1 for recurrence and enrichment in systems analyses. In Aim 3, Dr. Olfson will expand her skill set in iPSC brain organoids to assess early neurodevelopmental mechanisms of BFRBs. We will characterize iPSC brain organoids derived from 4 patients and unaffected sex-matched first- degree relatives to compare (i) neural differentiation and (ii) transcriptomics by single-cell RNA-sequencing. Overall, this K08 proposal will not only improve our fundamental knowledge of BFRB neurobiology, but also provide Dr. Olfson with vital training necessary to develop an independent neurogenomics research program to continue her investigations of BFRBs and other neuropsychiatric conditions. This training plan involves a multi-disciplinary mentoring team based primarily at the Yale Child Study Center with expertise in genomics (Dr. Fernandez and Dr. Scharf), iSPC brain organoids (Dr. Vaccarino and Dr. Fernandez), and BFRBs (Dr. Bloch and Dr. Scharf). Collectively, these mentors will provide Dr. Olfson with guidance and support to ensure her success in becoming an independent physician-scientist in translational neurogenomics.