Firstly, we screened the genes that are affected by the rare CNVs greater than 100 kb (described above). To do this we mapped all genomic coordinates for SNPs used in defining CNVs into the most updated human genome variation build (Ensembl variation build 50_36l, dbSNP build 129). We then aligned the genomic coordinates of the rare CNVs with the most updated human genome build (Ensembl core build 50_36l, human genome build 36). Any protein-coding gene that was either broken by or fully included in a rare CNV was considered “affected”. We detected the following gene counts that were affected by deletions in cases and controls respectively in the different populations: Aberdeen: 407, 210; Munich: 109,55; US: 70,159;and for duplications, Aberdeen: 294,180; Munich: 217,127; US: 34,17. We then used Ingenuity Pathway Analysis (IPA, see [21]) to perform a pathway enrichment (over-presenting) analysis separately for the four groups of genes we detected. The statistical significance was evaluated using Fisher's exact test. To avoid false positives, we further stipulated that at least two genes in a pathway must be disrupted for that pathway to be considered enriched, in addition to the P values from Fisher's exact test.
