Functional Enrichment of asQTLs
To compare the asQTL variants to a null distribution of similar variants without splicing association, we sampled genetic variants in the same cis-window of 1 Mb surrounding the transcription start site (TSS) and matched them to alternative splicing variants with respect to relative distance to TSS (within 5 kb) and minor allele frequency (within 2%). The variant effect predictor (VEP)22 tool from Ensembl was modified to produce custom tags that were STOP_GAINED, SPLICE_DONOR, SPLICE_ACCEPTOR, and FRAME_SHIFT. This modified version of VEP was applied to the imputed genotypes using the GENCODE v.1218 annotation. To this we added information of overlap with chromatin states23 and the Ensembl regulatory build,24 which constituted our functional annotation. The enrichment for a given category was calculated as the proportion between number regulatory associations in a given category and all regulatory variants over the same proportion in the null distribution of variants. The p value for this enrichment is calculated with the Fisher exact test.