CRS: Genome-Wide Dosage Sensitivity Analyses.

The CNV Risk Score (CRS) reflects the probability of intolerance to haploinsufficiency of each gene in the genome that is encapsulated in every CNV identified in an individual, regardless of the population prevalence of the mutation(15-17). In this study, the CRS was calculated as the sum of 1/LOEUF for deletions (CRS_del) and duplications (CRS_dup) separately using our previously published annotation pipeline (see Figure 1). Briefly, each coding gene with all isoforms fully encompassed in filtered CNVs was identified using ENSEMBL map (hg19)(33) and was annotated using the inverse LOEUF (1/LOEUF) score (gnomAD version 2.1.1)(18), which is available for 19,197 genes and ranges from 0.5 (gene tolerant to haploinsufficiency) to 33.3 (gene intolerant to haploinsufficiency). A score of 0 was assigned to individuals with no coding genes encompassed in any CNV. We tested the genome-wide CNV burden with logistic regression models:

β₀, β₁, β₂ and β₃ are the vectors of coefficients for fixed effects. The logistic regression models were computed using the glm() function in R.