of each other (Supplementary Fig. 6). Resulting significant CNVRs were excluded if they were (1) residing on telomere or centromere proximal cytobands; (2) arising from a ‘peninsula’ of common CNV (Supplementary Fig. 7); (3) genomic regions with extremes in GC content27; or (4) samples contributing to multiple CNVRs. To adjust for siblings in the AGRE data, we calculated a permutation-based P value (×1,000), in which disease labels for siblings were permutated together. DAVID (Database for Annotation, Visualization, and Integrated Discovery)28 assessed the significance of functional annotation clustering. We considered loci significant between cases and controls (P < 0.05) where ACC discovery cases had overlapping variation, replicated in AGRE or were not observed in control subjects, and validated with another method (qPCR Roche Universal Probe Library using qBase29, MRC-Holland MLPA, and Affymetrix 5.0 from Broad). Statistical correction of five deletion and nine duplication CNVRs, on the basis of discovery cohort (ACC) significance and signal review is appropriate for our study (‘CNV Filtering Steps’ in Supplementary Materials).
