Genomics of OCD in Latin American Communities

项目总结/摘要 在这项研究中，我试图了解常见和罕见的遗传变异如何影响发展的风险。 强迫症（OCD）。强迫症是一种致残性精神疾病，其潜在原因尚不清楚 病理生理学，这阻碍了新的治疗和干预措施的发展。虽然有一个 明确的遗传贡献强迫症的风险，几十年的调查还没有产生可重复的，统计学上的 发现了高可信度风险基因的重大发现。在其他神经发育性精神障碍中 包括精神分裂症、注意力缺陷/多动障碍和自闭症在内的全基因组关联 目前，在大量受试者中进行的GWAS研究和全外显子组测序（WES）正在识别风险基因 和基因座，为新疗法铺平了道路。增加强迫症的样本量，并应用多组学 这种方法，将导致类似的进展，强迫症。值得注意的是，尽管NDD取得了进展，但迄今为止的研究 主要是在欧洲制药业（EA）的样本中进行的，所以我们对 这些疾病在非EA人群中的遗传结构。为了弥补这些差距，最终目标是 研究常见和罕见的有害变异在强迫症风险中的作用，我将致力于新兴的大规模WES 研究强迫症，在正在进行的常见变异研究合作，并收集和分析Latinx强迫症样本。 为了实现这些目标，在K99阶段，我将首先接受相关统计数据的培训并加以利用 遗传学方法使用适当的动力自闭症和其他精神疾病的样本，同时建立一个 Latinx强迫症队列。R 00阶段将侧重于OCD遗传数据的荟萃分析，包括Latinx队列， 使用完善的管道。这将增加识别强迫症风险基因和位点的能力， 利用基因发现的功能方法来研究涉及的途径、细胞类型和发育阶段 强迫症风险此外，由于交叉疾病风险的研究是一个机会，以加强基因发现， 结合数据集，在R 00阶段，将在探索性研究中利用精神疾病之间的共享风险 强迫症基因和位点发现工作的分析。最终，我计划获得一个终身教职 并启动一个实验室，专注于遗传学和神经生物学方法的整合，以发现 NDD的潜在机制。这些努力将开始与强迫症，使用全基因组技术和杠杆作用， 混合和多样化的人群，并扩展到其他NDD。我还将利用K99阶段加深 知识撰写手稿和赠款，并提高技能，提出复杂的研究，以混合 和特殊观众。

Project Summary/Abstract In this study I seek to understand how common and rare genetic variation influence the risk of developing obsessive-compulsive disorder (OCD). OCD is a disabling psychiatric disorder with as yet unclear underlying pathophysiology, which has hindered the development of new treatments and interventions. While there is a clear genetic contribution to OCD risk, decades of investigations have yet to yield reproducible, statistically significant findings that identify high-confidence risk genes. In other neurodevelopmental psychiatric disorders (NDDs), including schizophrenia, attention-deficit/hyperactivity disorder and autism, genome-wide association studies (GWAS) and whole exome sequencing (WES) in large numbers of subjects are now identifying risk genes and loci, paving the way for novel therapeutics. Increasing sample sizes in OCD, and applying multi-omic approaches, will lead to similar advances in OCD. Of note, in spite of the advances in NDDs, studies to date were primarily carried out in samples of European Ancestry (EA), so we know comparatively less about the genetic architecture of these disorders in non-EA populations. To address these gaps, with the ultimate goal of studying the role of common and rare deleterious variation in OCD risk, I will work on emerging, large-scale WES studies in OCD, collaborate in ongoing common variant studies, and collect and analyze Latinx OCD samples. To achieve these goals, during the K99 phase, I will first be trained on, and make use of, relevant statistical genetic methods using suitably powered samples of autism and other psychiatric disorders, while building a Latinx OCD cohort. The R00 phase will focus on meta-analyses of OCD genetic data, including the Latinx cohort, using well-established pipelines. This will increase power to identify OCD risk genes and loci, and will enable functional approaches using gene findings to study pathways, cell-types and developmental stages implicated in OCD risk. Furthermore, since studies of cross-disorder risk are an opportunity to enhance gene discovery by combining datasets, in the R00 phase shared risk between psychiatric disorders will be leveraged in exploratory analyses in the OCD gene and locus discovery efforts. Ultimately, I plan to obtain a tenure-track faculty position and launch a laboratory that focuses on the integration of genetics and neurobiological approaches, to discover mechanisms underlying NDDs. These efforts will begin with OCD, using genome-wide techniques and leveraging admixed and diverse populations, and expand into other NDDs. I will also use the K99 phase to deepen knowledge in writing manuscripts and grants, and to improve skills in presenting complex studies to both mixed and specialty audiences.