The 16p11.2 and 22q11.2 copy number variants (CNVs) are associated with neurobehavioral traits including autism spectrum disorder (ASD), schizophrenia, bipolar disorder, obesity, and intellectual disability. Identifying specific genes contributing to each disorder and dissecting the architecture of CNV-trait association has been difficult, inspiring hypotheses of more complex models, such as the effects of pairs of genes. We generated pairwise expression imputation models for CNV genes and then applied these models to GWAS for: ASD, bipolar disorder, schizophrenia, BMI (obesity), and IQ (intellectual disability). We compared the trait variance explained by pairs with the variance explained with single genes and with traditional interaction models. We also modeled polygene region-wide effects using summed ranks across all genes in the region. In all CNV-trait pairs except for bipolar disorder at 22q11.2, pairwise effects explain more variance than single genes, which was specific to the CNV region for all 16p11.2 traits and ASD at 22q11.2. We identified individual genes over-represented in top pairs that did not show single-gene signal. We also found that BMI and IQ have a significant association with a regionwide score. Genetic architecture differs by trait and region, but 9/10 CNV-trait combinations showed evidence for multigene contribution, and for most of these, the importance of combinatorial models appeared unique to CNV regions. Our findings suggest that mechanistic insights for CNV pathology may require combinational models.

The authors have declared no competing interest.

This work was supported by National Institute of Mental Health R01 MH107467 to LAW. The funding body had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Individual-level genotypes for Psychiatric Genomics Consortium cohorts can be obtained by applying at www.pgc.unc.edu/ Summary level data from the PGC is at https://pgc.unc.edu/for-researchers/download-results/ . Summary-level genetic datasets for BMI and IQ are available to freely download from GIANT BMI (https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium) and CNCR IQ (https://ctg.cncr.nl/software/summary_statistics). Individual-level UK Biobank data can be obtained by application at https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access PrediXcan single-gene genome-wide models are available to download at predictdb.org. GTEx genotypes and phenotypes are requestable on dbGAP (phs000424.v8.p2). Summary statistics from association studies performed in this article are located in the supplement.