An integrative approach to linking genes, brain, and behavior in 22q11.2 CNV's

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PROJECT SUMMARY / ABSTRACT A primary challenge in uncovering biological mechanisms of developmental neuropsychiatric illnesses like schizophrenia (SCZ) and autism spectrum disorders (ASD) is grappling with their remarkable genetic and phenotypic heterogeneity. As such, taking a `genetics first' approach—i.e., ascertainment and comprehensive phenotyping of individuals with specific, known genetic variants—offers an alternative, biologically-tractable framework to dissecting genetic mechanisms underlying intermediate phenotypes of brain development, cognition, and behavior. Copy number variants (deleted or duplicated DNA segments ≥ 50 basepairs; CNVs) at the 22q11.2 locus are especially compelling models because they confer some of the largest known genetic risk for psychiatric disorders and include highly conserved genes critical for brain and cognitive development. The 22q11.2 deletion results from a 1.5–3 Mb hemizygous deletion on the long arm of chromosome 22 and has an estimated prevalence of 1 in 3,000–4,000 live births. In addition to medical comorbidities, the deletion is one of the greatest known genetic risks for SCZ, with a 25-fold risk increase compared to the general population. It is also associated with greater risk for other developmental neuropsychiatric disorders such as ASD. Yet, very little is known about the reciprocal 22q11.2 duplication phenotype, in part due to its more recent discovery as a recurrent CNV. While the phenotype is highly variable, it appears to confer high risk for ASD and specific language impairment. Intriguingly, multiple population-based studies have now shown the duplication to be significantly less common in SCZ cases than in the general population, suggesting the first putative protective mutation for SCZ. This notable distinction between risk and protective factors for SCZ suggests that gene-dosage specificity may underlie disease evolution. This project will leverage a large cohort of extensively phenotyped individuals with 22q11.2 deletions (n=91) or duplications (n=34), as well as demographically comparable controls (n=82). This will be the first study to investigate reciprocal effects of 22q11.2 CNVs on gene expression, brain, and behavior. Specifically, our aims are to: (i) establish the effect of 22q11.2 CNVs on multiple cognitive and behavioral measures relevant to SCZ and/or ASD (Aim 1), (ii) investigate transcriptome-wide dysregulation of gene expression by identifying networks of co-expressed genes resulting from a 22q11.2 deletion versus duplication and use enrichment analysis to infer dysregulated biological pathways (Aim 2), and (iii) probe biological pathways predictive of brain and behavioral phenotypes in these reciprocal CNVs (Aim 3). This integrative, multimodal approach aims to elucidate biological pathways and brain biomarkers which may differentiate risk versus protective factors for psychosis or converging factors for ASD risk, in the context of this highly-penetrant CNV, with the primary goal of providing novel insights into how these CNVs disrupt the brain and contribute to disease pathogenesis.