Genomics of OCD in Latin American Communities

拉丁美洲社区强迫症的基因组学

• 批准号: 10591747
• 负责人: Carolina Cappi
• 金额: $ 12.61万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-07 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591747
• 关键词: Acceleration; Address; Algorithms; Architecture; Attention deficit hyperactivity disorder; Biological; Bipolar Disorder; Code; Collaborations; Collection; Communities; Complex; Data; Data Aggregation; Data Set; Development; Diagnosis; Disease; Ensure; Etiology; European ancestry; Explosion; Faculty; Focus Groups; Functional disorder; Future; Gene Expression; Genes; Genetic; Genetic Diseases; Genetic Research; Genetic Risk; Genetic Variation; Genetic study; Genomics; Genotype; Goals; Grant; Inherited; Intervention; Investigation; Knowledge; Laboratories; Latin American; Latinx; Latinx population; Lead; Learning; Manuscripts; Maps; Mental Depression; Mental disorders; Mentors; Meta-Analysis; Methods; Neurobiology; Neurons; Obsessive-Compulsive Disorder; Parents; Pathway interactions; Phase; Phenotype; Population; Population Heterogeneity; Positioning Attribute; Post-Traumatic Stress Disorders; Reporting; Reproducibility; Research; Risk; Role; Sample Size; Sampling; Schizophrenia; Scoring Method; Severities; Symptoms; Techniques; Training; Variant; Work; Writing; autism spectrum disorder; cell type; cohort; comparative; de novo mutation; disorder risk; exome sequencing; gene discovery; genetic architecture; genetic variant; genome wide association study; genome-wide; genomic data; improved; insight; medical specialties; multiple omics; novel therapeutics; polygenic risk score; programs; psychiatric genomics; psychogenetics; risk sharing; risk variant; skills; tenure track; working group

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.

项目概要/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罹患癌症的风险 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，这阻碍了新疗法和干预措施的发展。虽然有一个 虽然遗传对强迫症风险有明显的影响，但数十年的研究尚未得出可重复的、统计的结果 识别高可信度风险基因的重大发现。在其他神经发育精神疾病中 (NDD)，包括精神分裂症、注意力缺陷/多动症和自闭症、全基因组关联 对大量受试者的研究（GWAS）和全外显子组测序（WES）现在正在识别风险基因 和位点，为新疗法铺平道路。增加强迫症的样本量，并应用多组学 方法，将导致强迫症的类似进展。值得注意的是，尽管 NDD 取得了进展，但迄今为止的研究 主要是在欧洲血统（EA）样本中进行的，因此我们对 非 EA 人群中这些疾病的遗传结构。为了解决这些差距，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，合作进行正在进行的常见变异研究，并收集和分析拉丁强迫症样本。 为了实现这些目标，在K99阶段，我将首先接受相关统计的培训并利用这些数据 使用适当动力的自闭症和其他精神疾病样本的遗传方法，同时建立一个 拉丁裔强迫症队列。 R00 阶段将重点关注强迫症遗传数据的荟萃分析，包括拉丁裔队列、 使用完善的管道。这将增强识别强迫症风险基因和基因座的能力，并使 利用基因发现来研究相关途径、细胞类型和发育阶段的功能方法 强迫症风险。此外，由于跨疾病风险的研究是通过以下方式增强基因发现的机会 结合数据集，在 R00 阶段，精神疾病之间的共同风险将被用于探索性研究 强迫症基因和基因座发现工作的分析。最终，我计划获得终身教职 并成立一个专注于遗传学和神经生物学方法整合的实验室，以发现 NDD 的潜在机制。这些努力将从强迫症开始，使用全基因组技术并利用 混合和多样化的人群，并扩展到其他 NDD。我也会用K99阶段来加深 撰写手稿和资助的知识，并提高向混合和混合的人展示复杂研究的技能 和专业观众。