Schizophrenia spectrum disorders (SSDs) are characterized by substantial clinical and genetic heterogeneity. Multiple recurrent copy number variants (CNVs) increase risk for SSDs; however, how known risk CNVs and broader genome-wide CNVs influence clinical variability is unclear. The current study examined associations between borderline intellectual functioning or childhood-onset psychosis, known risk CNVs, and burden of deletions affecting genes in 18 previously validated neurodevelopmental gene-sets in 618 SSD individuals. CNV associations were assessed for replication in 235 SSD relatives and 583 controls, and 9,930 youth from the Adolescent Brain Cognitive Development (ABCD) Study. Known SSD- and neurodevelopmental disorder (NDD)-risk CNVs were associated with borderline intellectual functioning in SSD cases (odds ratios (OR) = 7.09 and 4.57, respectively); NDD-risk deletions were nominally associated with childhood-onset psychosis (OR = 4.34). Furthermore, deletion of genes involved in regulating gene expression during fetal brain development was associated with borderline intellectual functioning across SSD cases and non-cases (OR = 2.58), with partial replication in the ABCD cohort. Exploratory analyses of cortical morphology showed associations between fetal gene regulatory gene deletions and altered gray matter volume and cortical thickness across cohorts. Results highlight contributions of known risk CNVs to phenotypic variability in SSD and the utility of a neurodevelopmental framework for identifying mechanisms that influence phenotypic variability in SSDs, as well as the broader population, with implications for personalized medicine approaches to care.

RAIB, JS and AFA-B are co-founders of Centile Bioscience. RAIB and JS additionally serve as directors for Centile Bioscience Inc. and Ltd.

This work was supported by NIMH (K08 MH118577 to JKF; MH101506 to KHK; R01 MH37705, R01 MH110544 and P50 MH066286 to KHN; U01 MH082004 to DOP; U01 MH082004 to TDC; U01 MH081988 to EFW; R37 MH085953, U01 MH081902, P50 MH066286, R01 MH129858, U01 MH124639, R01 MH123575, and U01 MH119736 to CEB; F31 MH119786 to CKD; F31 MH124421 to AG), the Brain & Behavior Research Foundation (NARSAD Young Investigator Award to JKF), the National Center for Advancing Translational Sciences UCLA CTSI Grant UL1TR001881 (Award to CEB & JKF), the UCLA Brain Research Institute (Postdoctoral Award to JKF), and the Shear Family Foundation.

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