Figure 3  Enrichment of Functional Gene Sets Affected by Rare Exonic CNVs in Affected versus Control Subjects
Overrepresentation of deletions (A) and duplications (B) in various functional gene sets. ORs, with 95% CIs, and the percentages of affected subjects (n = 1,486) and control subjects (n = 1,820) with exonic CNVs overlapping genes are given for the following gene sets: (1) highly-brain-expressed genes (log(RPKM) > 4.5, BrainSpan; n = 5,610); (2) functionally characterized control genes not expressed in the brain (log(RPKM) < 1, BrainSpan; n = 5,410); (3) PSD genes (n = 1,453);33 (4) FMRP interactors (n = 842);34 (5) genes associated with neurological phenotypes compiled from the HPO and MPO (n = 3,112); (6) genes as described in (5) but filtered for autosomal-dominant genes (n = 739); and (7) genes grouped by their pHI35 into three subgroups: pHI > 0.15 (n = 8,862), pHI > 0.35 (n = 4,136,) and pHI > 0.55 (n = 2,214). Genes with a pHI > 0.35 were considered haploinsufficient. The p values for affected and control subjects were estimated with two-tailed Fisher’s exact tests (∗p < 0.01, ∗∗p < 0.001, ∗∗∗p < 0.0001).
(C–D) Pattern of increased burden as the number of brain-expressed genes affected by deletions (C) or duplications (D) increased. The percentages of affected and control subjects with CNVs overlapping genes are shown for deletions and duplications separately. For estimating the expected ORs (stars), a logit model of case status (affected or control) was fit to covariates, namely CNV status, the number of genes covered by each CNV, and their average brain expression levels (neocortex, BrainSpan). See Tables S11A–S11E for the results of alternative models, all of which showed that ASD risk increased as a function of the number of brain-expressed genes affected by a CNV, even after within-subject dependency of CNVs was accounted for.