Most of the TWAS associations are the result of differential intron usage, suggesting the importance of pre-mRNA splicing in Alzheimer’s disease (Fig. 5a). An example of TWAS association with intron usage at PTK2B, a known Alzheimer’s disease susceptibility locus, is shown in Fig. 5d. We often observed multiple TWAS-associated genes in the same locus, likely due to co-expression of genes in close physical proximity or allelic heterogeneity within the susceptibility locus40. To account for multiple associations in the same locus, we applied conditional and joint association methods that rely on summary statistics40,41 to identify genes that had significant TWAS associations when analyzed jointly (Figs. 5e and 6b). A region with multiple TWAS association includes the PTK2B/CLU locus, which shows independent co-localized association for both GWAS14 and splicing effects (Fig. 5e).
