Splicing of pre-mRNA is catalyzed by a large ribonucleoprotein complex called the spliceosome, which consists of five snRNAs and numerous splicing factors33. To identify brain splicing factors that regulate sQTL events in trans, we evaluated whether the lead sQTL SNPs identified in our study are enriched in RBP binding sites using publicly available cross-linking immunoprecipitation (CLIP)-Seq datasets from 76 RBPs in CLIPdb34. We found that binding targets of 18 RBPs are significantly enriched among lead sQTLs (Fig. 4a). The most enriched RBP is PTBP1, followed by HNRNPC, CPSF7, and ELAVL1 (P < 0.05, Fisher’s exact test with Benjamini-Hochberg correction). Notably, the enrichment for neuronal ELAVL1 RBP target sites is consistent with a recent report that, upon neuronal ELAVL1 depletion, BIN1 and PICALM transcripts were found to have lower exon inclusion for those sites in which ELAVL binding sites directly overlapped with SNPs associated with Alzheimer’s disease35.
