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， 双相情感障碍，他们强烈地促进他们的公共卫生负担。虽然分类不同，但这些 精神健康状况有几个共同点，包括强大的遗传基础和身体缺陷， 跨诊断的神经系统领域，包括昼夜节律，NIMH Re的关键组成部分， 搜索域标准（RDoC）。尽管有这些共性，但这些诊断也有异质性- 在临床和遗传水平上的一致性;即使在共享的个体之间也存在显著的表型变异性。 同样的诊断，虽然罕见的遗传变异可以在10-30%的人中共同确定， 在这些诊断中，没有一个个体罕见变异占病例的1%以上。因此，有一个关键- 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方法 战略，以了解特定的维度行为域，如昼夜节律异常。 我们将重点关注一种罕见的复发性基因拷贝数变异（CNV），它与自闭症有关 和精神分裂症，并且包括人LHX 1：17 q12 CNV。Lhx 1控制通信， 下丘脑视交叉上核（SCN）主生物钟中的神经元之间通过 肽，也是该系统的耦合强度的动态调节剂。在17 q12 CNV患者中， 涉及包含15个基因的相同遗传区域，其中包括LHX 1，便于比较， 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， 与睡眠异常相关的疾病，同时建立在已知的分子机制上， 控制哺乳动物生理机能的生物系统。为此，我们将研究神经行为学- caland dimensional心理健康和昼夜表型的40名年轻人（年龄9至25岁）， 17 q12中有40个重复。评估包括一系列措施，包括诊断- 访谈，认知测试，睡眠监测与一周的活动记录，和昼夜节律相评估， 暗光褪黑激素起效（DLMO）。我们还将进行多基因风险评分分析的基因组测序 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17 q12 CNVs相关的神经行为和昼夜节律表型，作为三维模型， 在精准医学时代，研究其他个别罕见但集体常见的遗传风险因素。