Our study also offers insights for several well-known Alzheimer’s disease loci in which the gene was known but the functional mechanism remained unclear. Similar to our work in CD3316, the careful analysis of these cortical data highlights a specific splicing mechanism for the Alzheimer’s disease risk alleles at CLU, PICALM, and PTK2B. All three are complex proteins with a large number of exons, so our results prioritize specific domains in these proteins as harboring the functional domain that influences Alzheimer’s disease risk. Further, our analyses of RBP involved in splicing regulation of Alzheimer’s disease susceptibility genes including PICALM, and RNA binding site analysis of HNRNPC (Fig. 4c; Supplementary Fig. 6) and ELAVL helps to prioritize the variant that may be driving the genetic association and to elaborate the series of events upstream of the susceptibility variant that enable its expression. Thus, our catalog of splicing variants made available with this study provides a starting point for further focused molecular and biochemical experimental validation to fully elucidate the role of these splicing variants in the etiology of Alzheimer’s disease.
