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Deletions and duplications of the 16p11.2 and 22q11.2 copy number variant (CNV) regions are associated with brain-related disorders including autism spectrum disorder, schizophrenia, bipolar disorder, obesity, and intellectual disability. The contribution of individual genes in each CNV to each phenotype is unknown. We propose a novel in silico approach to systematically interrogate each gene's effect on brain-related disorders. As CNVs affect RNA copy number, we attempted to fine-map each CNV region by asking whether natural gene expression variation in any individual gene would increase risk for the same disorder(s). We first used large genotyped cohorts for five CNV-associated traits: autism spectrum disorder, schizophrenia, bipolar disorder, BMI, and IQ. Imputing the transcriptome from the genome, we performed association testing for CNV genes with the genotype datasets. We found individual genes within 16p11.2 associated with schizophrenia (TMEM219, INO80E, YPEL3), BMI (TMEM219, SPN, TAOK2,INO80E), and IQ (SPN), with independent replication. Using a conditional analysis, we showed that INO80E explains the schizophrenia association. Second, we used a biobank containing electronic health data and genotypes for 23,000 individuals to perform phenome-wide association studies with predicted expressions of 16p11.2 and 22q11.2 genes and over 1,500 health traits, finding eight significant gene-trait pairs. Third, we compared the medical phenome of CNV carriers to controls within an independent group of 3 million individuals. We identified CNV traits may have indicated genetic testing, other traits previously observed in CNV carriers, and novel traits. Our results provide new insight into the contribution of individual CNV genes to CNV-associated traits. ### Competing Interest Statement The authors have declared no competing interest.

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