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/摘要 睡眠异常是许多心理健康状况的标志，包括自闭症，精神分裂症和 双相情感障碍，他们为公共健康负担做出了巨大贡献。尽管绝对与众不同，但 心理健康状况有几种共同点，包括强大的遗传基础和障碍 跨越诊断的范围域，包括昼夜节律，这是NIMH重新构成的关键组成部分 搜索域标准（RDOC）。尽管有这些共同点，但这些诊断也以异性危机为特征 在临床和遗传水平上的NEITY；即使在分享的个人中，也有明显的表型变异性 同样的诊断，尽管可以在10-30％的患有10-30％ 这些诊断，没有个体稀有变体占病例的1％以上。因此，有一个批评 对减少这种遗传异质性的研究方法的需求，并提供更直接的生物学 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的经常性遗传拷贝数变体（CNV） 和精神分裂症，其中包括人类LHX1：17Q12 CNV。 LHX1控制沟通 - 通过下丘脑的上核（SCN）中的昼夜节律大师时钟中的补间神经元通过 肽，也是该系统耦合强度的动态调节剂。在有17q12 CNV的个人中 涉及15个基因的同一遗传区域，其中包括LHX1，促进了比较和 为调查潜在基因剂量对昼夜节律生物学的影响打开大门。 在这项研究中，我们旨在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械上 在哺乳动物中控制昼夜节律功能的nism。为此，我们将研究神经行为分类 CAL和维度的心理健康以及40名年轻人（9至25岁）的昼夜节律表型 Letions和40在2012年第17季度重复。评估包括一系列措施，包括诊断性 电视，认知测试，一周的Actraphy的睡眠监测以及昼夜节律评估 昏暗的光褪黑激素发作（DLMO）。我们还将对多基因风险评分分析进行基因组测序 确定表型变异性的其他遗传因素。这些结果将使我们能够识别关键 与17q12 CNV相关的神经行为和昼夜节律表型，作为维度的模型 在精密医学时代，对其他罕见但共同常见的遗传危险因素的研究。