Impact of 17q12 CNVs Associated with Autism on Circadian and Sleep Phenotypes

与自闭症相关的 17q12 CNV 对昼夜节律和睡眠表型的影响

• 批准号: 10090151
• 负责人: Daniel Moreno De Luca
• 金额: $ 21.62万
• 依托单位: EMMA PENDLETON BRADLEY HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-06 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10090151
• 关键词: 17q12; Adolescent; Age; Anatomy; Animal Model; Animals; Behavioral; Biochemical; Biological; Biology; Bipolar Disorder; Body Temperature; Categories; Centers of Research Excellence; Child; Circadian Rhythms; Communication; Copy Number Polymorphism; Coupling; Data; Diagnosis; Diagnostic; Dimensions; Disease; Frequencies; Gene Dosage; General Population; Genes; Genetic; Genetic Heterogeneity; Genetic Variation; Heterogeneity; High Prevalence; Human; Hypothalamic structure; Impaired cognition; Impairment; Individual; International; Interview; Investigation; LHX1 gene; Light; Mammals; Measures; Medical Genetics; Medical Records; Melatonin; Mental Health; Mentorship; Modeling; Molecular; Mutation; National Institute of Mental Health; Neurons; Outcome; Participant; Patients; Penetrance; Peptides; Performance; Phase; Phenotype; Polysomnography; Population; Psychiatric Diagnosis; Public Health; Publishing; Questionnaires; Recurrence; Research; Role; Schizophrenia; Sleep; System; Testing; Time; Tweens; Work; actigraphy; autism spectrum disorder; base; behavioral phenotyping; circadian; circadian pacemaker; cognitive testing; endophenotype; feeding; genetic risk factor; genetic variant; genome sequencing; high risk; induced pluripotent stem cell; neurobehavioral; neuropsychiatry; polygenic risk score; precision medicine; rare variant; sleep abnormalities; sleep onset; social; social deficits; stem; stem cell model; suprachiasmatic nucleus; trait

PROJECT ABSTRACT/SUMMARY Sleep abnormalities are a hallmark of many mental health conditions including autism, schizophrenia, and bipolar disorder, and they strongly contribute to their public health burden. Although categorically distinct, these mental health conditions have several commonalities, including a strong genetic basis and impairments in be- havioral domains that span across diagnoses, including circadian rhythms, a key component of the NIMH Re- search Domain Criteria (RDoC). Despite these commonalities, these diagnoses are also marked by heteroge- neity at the clinical and genetic levels; there is marked phenotypic variability even among individuals who share the same diagnosis, and although rare genetic variants can collectively be identified in 10-30% of people with these diagnoses, no individual rare variant accounts for more than 1% of the cases. Therefore, there is a criti- cal need for research approaches that reduce this genetic heterogeneity and offer a more direct biological strategy to understand the specific dimensional behavioral domains, such as circadian rhythm abnormalities. We will focus on a rare recurrent genetic copy number variant (CNV) that has been associated with autism and schizophrenia and which includes the human LHX1: 17q12 CNVs. Lhx1 controls the communication be- tween neurons in the master circadian clock in the suprachiasmatic nuclei (SCN) of the hypothalamus through peptides, and is also a dynamic regulator of coupling strength of this system. In individuals with 17q12 CNV, the same genetic region encompassing 15 genes, among them LHX1, is involved, facilitating comparisons and opening the door for the investigation of potential gene dosage effects on circadian biology. In this study, we aim to capitalize on the strengths of reducing the genetic heterogeneity of mental health conditions associated with sleep abnormalities, while simultaneously building on the known molecular mecha- nisms that govern circadian function in mammals. For this purpose, we will study the neurobehavioral categori- cal and dimensional mental health and circadian phenotypes of 40 young people (ages 9 to 25 years) with de- letions and 40 with duplications in 17q12. Assessments include an array of measures, including diagnostic in- terviews, cognitive tests, sleep monitoring with one-week of actigraphy, and circadian phase assessment with dim light melatonin onset (DLMO). We will also perform genome sequencing for polygenic risk score analyses to identify additional genetic contributors of phenotypic variability. These results will allow us to identify key neurobehavioral and circadian phenotypes associated with 17q12 CNVs, serving as a model for dimensional studies of other individually rare but collectively common genetic risk factors in the era of precision medicine.

项目摘要/总结 睡眠异常是许多精神健康状况的标志，包括自闭症、精神分裂症和 双相情感障碍，他们极大地加重了公共卫生负担。尽管绝对不同，但这些 心理健康状况有几个共同点，包括强大的遗传基础和行为障碍。 跨越诊断的行为领域，包括昼夜节律，这是 NIMH Re 的一个关键组成部分。 搜索域标准 (RDoC)。尽管有这些共同点，这些诊断也具有异质性 临床和遗传水平上的密切性；即使在具有相同特征的个体之间也存在明显的表型变异 相同的诊断，尽管罕见的基因变异可以在 10-30% 的患者中共同鉴定出来 这些诊断中，没有任何一种罕见变异占病例的1%以上。因此，有一个批判 我们需要研究方法来减少这种遗传异质性并提供更直接的生物学研究 了解特定维度行为领域的策略，例如昼夜节律异常。 我们将重点关注与自闭症相关的罕见复发性基因拷贝数变异 (CNV) 和精神分裂症，其中包括人类 LHX1：17q12 CNV。 Lhx1 控制通信be- 下丘脑视交叉上核 (SCN) 中主生物钟的神经元之间通过 肽，也是该系统耦合强度的动态调节剂。在具有 17q12 CNV 的个体中， 涉及包含 15 个基因（其中包括 LHX1）的同一遗传区域，便于比较和 为研究基因剂量对昼夜节律生物学的潜在影响打开了大门。 在这项研究中，我们的目标是利用减少心理健康遗传异质性的优势 与睡眠异常相关的条件，同时建立在已知的分子机制之上 控制哺乳动物昼夜节律功能的机制。为此，我们将研究神经行为类别 40 名青少年（9 至 25 岁）的心理健康和昼夜节律表型 letions 和 40 在 17q12 中有重复。评估包括一系列措施，包括诊断信息 访谈、认知测试、为期一周的体动记录仪睡眠监测以及昼夜节律阶段评估 弱光褪黑激素启动（DLMO）。我们还将进行基因组测序以进行多基因风险评分分析 以确定表型变异的其他遗传因素。这些结果将使我们能够确定关键 与 17q12 CNV 相关的神经行为和昼夜节律表型，作为维度模型 对精准医学时代其他个别罕见但共同常见的遗传风险因素的研究。