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Chunk #21 — RESULTS — TWAS prioritizes Alzheimer’s disease genes in autophagy pathways

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Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer's disease susceptibility.
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To replicate these results, we first assessed whether an expression imputation model built using the CMC dataset28 that was then deployed in the IGAP GWAS yields similar results. We focused on the 21 significantly associated genes above: four genes (CR1, PTK2B, TBC1D7, and SH3YL1) replicated at FDR < 0.05 and two genes (AP2A1 and PHKB) were suggestive at P < 0.05 with the expression and splicing inference from CMC (Fig. 5b). The directions of effect for all six associations were consistent in both datasets (Fig. 5b). Thus, we see replication of our results: they are not due to the unique properties of the ROSMAP dataset. Second, we used a different Alzheimer’s disease GWAS - the UK BioBank (UKBB) GWAS by proxy39 - to replicate the IGAP TWAS results. We note that, despite analyzing data from 116,196 subjects, the UKBB GWAS is underpowered since the GWAS does not use Alzheimer’s disease cases but, rather, subjects who have a first-degree relative with Alzheimer’s disease as “cases”. Nevertheless, we were able to replicate (at a nominal P < 0.05) seven of our IGAP