Chunk #73 — STAR* METHODS — QUANTIFICATION AND STATISTICAL ANALYSIS — Relationship of Lead SNPs from Meta-analysis to Rare CNVs and Mutations Previously Associated with Neurodevelopmental Genomic Disorders
We conducted additional analyses to determine whether our 146 genome-wide significant loci are enriched in CNVs spanning defined genomic disorder (GD) regions or damaging mutations previously shown to be associated with neurodevelopmental disorders (including autism spectrum disorder, intellectual disability, and developmental delay), also known as genomic disorders (GDs). The reference data comprise a curated set of 51 GD loci (encompassing 823 protein-coding genes) with multiple reports of ASD/ID/DD-associated CNVs (Satterstrom et al., 2019). The GD curation process is described in the original publication. Each of our 146 lead SNPs were assigned to its candidate genes using various functional genomics datasets including Hi-C data, overlap with gene and regulatory elements. We examined all SNPs as well as dividing SNPs into groups based on their degree of pleiotropic association and conducted permutation testing to assess significant enrichment. Permutation testing was performed by first assigning each lead (sentinel) SNP to the nearest gene, then randomly sampling 1,000 new genes from the genome with replacement while matching on chromosome and gene length. P-values were derived by comparing the empirically observed number of overlaps to the distribution of expected overlaps based on 1,000 matched permutations (Data S3.1).
