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.