PROJECT SUMMARY/ABSTRACT The remarkable heterogeneity of developmental neuropsychiatric disorders has been a major barrier for understanding disease mechanisms. Taking a ‘genetics first’ approach (i.e., ascertaining patients based on a known, homogeneous genetic etiology) may allow us to overcome the barriers posed by this complexity. Notably, a 1.5-2.6 Megabase deletion at the Chromosome 22q11.2 locus results in the most common known microdeletion disorder, 22q11.2 Deletion Syndrome (22qDel), which is among the greatest known genetic risk factors for schizophrenia (SCZ). As 22qDel can be detected very early in development, it allows a unique opportunity for prospective investigation of early biomarkers of psychosis, long before disease-related processes begin to unfold. Adding to the evidence that this genomic region is highly relevant to the development of psychosis, the reciprocal 22q11.2 duplication (22qDup) is significantly less common in SCZ cases than in the general population, suggesting the first putative protective mutation for SCZ. This proposal is for five years of funding to continue our prospective longitudinal study of mechanisms relevant to neuropsychiatric disease risk in 22q11.2 copy number variants (CNVs). Our work to date supports an emerging framework of a lifelong biological vulnerability in 22qDel due to haploinsufficiency for specific genes critical for brain development, in combination with background genetic risk. This vulnerability sets the stage for subsequent events during adolescence, including changes in dendritic arborization and increased disruption of thalamocortical circuitry (across sleep and wake), that lead to escalating clinical and cognitive manifestations. In this second competitive renewal application we propose to continue our accelerated longitudinal design, prospectively following our large cohort of youth with 22q11.2 deletions (n=90) through the highest risk period for illness onset, compared to both demographically comparable typically developing controls (n=45) and youth with reciprocal 22q11.2 duplications (n=45). Building on our previous findings, our primary goals are: (1) To investigate 22q11.2-related progressive abnormalities in structural and functional brain biomarkers associated with psychosis risk, in order to identify developmentally-specific periods of regional and circuit-specific structural and functional neuroanatomic changes; 2) Using novel methods for real-world assessment of sleep physiology (electroencephalogram headbands), to pursue the hypothesis that impoverished sleep spindle activity is linked with thalamocortical network disruption, observed via resting state functional MRI during wake, and increased psychotic symptomatology, suggesting a common mechanism; and (3) Given our findings that divergent psychosis risk is underpinned by opposing effects of 22qDel and 22qDup on brain structure, to probe mechanisms underlying 22q11.2 gene dosage effects on neurobehavioral phenotypes...