On the other hand, we also observed significant enrichment for the lead sQTL SNPs within the binding sites for a number of heterogeneous nuclear ribonucleoproteins (hnRNP), including hnRNP C (P < 0.009). Further, we find that the expression levels of hnRNP splicing factors are correlated with intronic excision levels of hundreds of genes, many of which are in Alzheimer’s disease susceptibility loci including BIN1, PICALM, APP, and CLU (Fig. 4b; Supplementary Figs. 7 and 8). The hnRNP C factor has been linked to Alzheimer’s disease in previous studies, including in a recent biochemical study reporting the translational regulation of APP mRNA by hnRNP C36. This observation goes towards the mechanism of the sQTL: consistent with the assumption that, altering the sequence of a binding site changes the likelihood that a splicing event occurs in vivo. In one example of an sQTL affecting intron usage, a SNP within intron of TBC1D7 is found within CLIP-defined binding sites for hnRNP C as well as other RBPs (Fig. 4c). Thus, incorporating RBP binding sites as a functional annotation allows for improving our accuracy
