Leveraging rare genetic etiologies to advance knowledge and treatment of neuropsychiatric disorders

项目摘要 神经精神障碍（NPD），如精神分裂症，双相情感障碍和自闭症是行为定义的 以及具有广泛严重性和结果的病因异质性病症。接受癌症和其他 常见疾病，罕见遗传性疾病的研究已经阐明了关键的病理生理机制， 导致显著的治疗进步。我们假设这种策略可以成功地应用于 NPD新的基因组技术导致发现了数百种罕见的遗传NPD， 在一些实施方案中，所述方法包括大效应量的单基因核苷酸变异（CNV）和单基因核苷酸变异（SNV）。然而，详细的神经精神病学 由于难以招募足够的队列，尚未建立大多数这些疾病的特征 大小来进行统计分析。我们将利用Geisinger的大量NPD临床人群， 华盛顿大学和圣路易斯的华盛顿大学招募患有罕见遗传疾病的个体 for this study研究.我们还将研究整个基因组中其他贡献者对变量的影响 神经精神症状在这些疾病中的表现力。本研究将系统地研究这些 罕见的遗传NPD方面通过以下目标：1）采用具有高度成本效益的，遗传学优先的 策略，以实现具有遗传性NPD病因的大型队列的基线表征。每一年， 作为精神病、发育和行为保健的一部分， 由罕见的遗传性NPD患者产生。我们将协调临床使用的核心评估组合， 我们希望利用这些高质量的数据，对超过1,000名先证者进行广泛的数据共享和分析， 大大降低了多维表型的研究成本。2)详细描述 在选定的罕见遗传NPD的表型签名，包括家庭背景的影响， 可变表现力。我们将描述所选罕见遗传性NPD的定量神经精神病学特征 （最初为1q21.1和15q13.3 CNV和CHD8 SNV）。所有这三种疾病都显示出了全基因组的意义 增加神经精神表型的风险，包括精神病，情绪障碍和自闭症。我们将 评估250名患有这些罕见遗传性NPD的先证者的行为、精神和认知特征， 探讨家庭背景对神经精神症状变量表达度的影响 症状3)评估常见和次要罕见基因组变异对可变 罕见遗传性NPD的表现力。通过两个子目标，我们将探讨共同（多基因风险）的影响 评分）和罕见（"第二次打击"）基因组贡献者对神经精神症状的风险或恢复力。 分析通过目标1和目标2收集的数据，以及更广泛地探索基因组和电子 Geisinger的MyCode队列中25万人的健康记录数据，我们将展示如何不同 基因组背景因素导致罕见遗传性NPD个体的临床异质性。这些 研究可能最终告知神经精神结果的个人水平的诊断。

PROJECT SUMMARY Neuropsychiatric disorders (NPD), such as schizophrenia, bipolar disorder, and autism are behaviorally-defined and etiologically-heterogeneous conditions with a wide range of severity and outcomes. For cancer and other common diseases, the study of rare genetic disorders has illuminated key pathophysiological mechanisms, resulting in significant treatment advances. We hypothesize that this strategy can be successfully applied to NPD. New genomic technologies have led to the discovery of hundreds of rare genetic NPD due to copy number (CNVs) and single gene nucleotide variants (SNVs) of large effect size. However, detailed neuropsychiatric profiles have not been established for most of these conditions, due in part to difficulty recruiting adequate cohort sizes to power statistical analyses. We will capitalize on large NPD clinical populations at Geisinger, the University of Washington, and Washington University in St. Louis to recruit individuals with rare genetic disorders for this study. We will also examine the influence of additional contributors throughout the genome to the variable expressivity of neuropsychiatric symptoms in these disorders. This study will systematically examine these aspects of rare genetic NPD through the following aims: 1) Employ a highly cost-effective, genetics-first strategy to achieve baseline characterization of a large cohort with genetic NPD etiologies. Every year, as part of psychiatric, developmental, and behavioral healthcare, valuable genotype and phenotype data are generated from individuals with rare genetic NPD. We will harmonize core assessment batteries used in clinical care to leverage this high-quality data for broad data sharing and analyses on >1,000 probands, accelerating discovery and greatly reducing the research cost of multidimensional phenotyping. 2) Describe detailed phenotypic signatures in selected rare genetic NPD, including the impact of family background on variable expressivity. We will characterize quantitative neuropsychiatric traits for selected rare genetic NPD (initially 1q21.1 and 15q13.3 CNVs and CHD8 SNVs). All three disorders have shown genome-wide significance for increased risk of neuropsychiatric phenotypes, including psychosis, mood disorders, and autism. We will assess behavioral, psychiatric, and cognitive traits in 250 probands with these rare genetic NPD and their first- degree family members to explore the impact of family background on variable expressivity of neuropsychiatric symptoms. 3) Assess the contributions of common and secondary rare genomic variants to variable expressivity in rare genetic NPD. Through two sub-aims, we will explore the impact of common (polygenic risk scores) and rare (`second hits') genomic contributors on risk or resilience for neuropsychiatric symptoms. Analyzing data collected through Aims 1 and 2, in addition to a broader exploration of genomic and electronic health record data from 250,000 individuals in Geisinger's MyCode cohort, we will demonstrate how different genomic background contributors lead to clinical heterogeneity in individuals with rare genetic NPD. These studies may eventually inform individual-level prognoses for neuropsychiatric outcomes.