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

项目摘要/摘要 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，他们极大地增加了他们的公共卫生负担。虽然绝对不同，但这些 精神健康状况有几个共性，包括强大的遗传基础和BE-BE的损害 跨越诊断的行为区域，包括昼夜节律，NIMH Re的关键组成部分 搜索域条件(RDoC)。尽管有这些共性，但这些诊断也具有异质性- 临床和遗传水平上的亲缘关系；即使在拥有相同基因的个体之间也存在明显的表型变异 同样的诊断，尽管罕见的基因变异可以在10%-30%的患有 这些诊断中，无个别罕见变异占病例的1%以上。因此，有一个标准-- 加州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 了解特定维度行为领域的策略，例如昼夜节律异常。 我们将重点关注一种与自闭症相关的罕见的反复发生的遗传拷贝数变异(CNV) 和精神分裂症，其中包括人类LHX1：17q12 CNV。Lhx1控制通信是- 下丘脑视交叉上核(SCN)主昼夜节律中的吐温神经元通过 也是该体系偶联强度的动态调节器。在携带17q12 CNV的个体中， 同一遗传区域包含15个基因，其中包括LHX1，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- 支配哺乳动物昼夜节律功能的神经。为此，我们将研究神经行为范畴- 40名9~25岁抑郁症患者的CAL和Dimension心理健康状况及昼夜节律表型 在17q12中有40例有重复。评估包括一系列措施，包括诊断- Terview、认知测试、一周活动记录仪的睡眠监测和昼夜节律阶段评估 暗淡的褪黑素发作(DLMO)。我们还将为多基因风险得分分析进行基因组测序 以确定表型变异的其他遗传贡献者。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，作为维度的模型 在精确医学时代，对其他个别罕见但共同的遗传风险因素的研究。

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.