All analyses included rare CNVs larger than 500 kb. The genome-wide burden of CNVs was first assessed according to the average number of CNVs per sample. Significance of the burden comparisons was assessed via permutation (100 000 permutations, one-sided test) using PLINK (version 1.06)25 with analyses undertaken for all rare, large CNVs as well as stratified according to CNV type (deletion or duplication). For locus-specific tests of association, we first defined test regions according to the genomic boundaries for each CNV identified in the entire sample. When several CNVs identified in different samples overlapped, they were merged to create one locus that encompassed all overlapping CNVs. We then established the number of CNVs present within each test region in the patients and controls. Our analyses are based on rates of CNVs per patient, but to facilitate clinical interpretation, we also provide results for the percentage of individuals carrying large, rare CNVs.
