Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer's disease susceptibility.

Nat Genet
Authors
Keywords
Abstract

Here we use deep sequencing to identify sources of variation in mRNA splicing in the dorsolateral prefrontal cortex (DLPFC) of 450 subjects from two aging cohorts. Hundreds of aberrant pre-mRNA splicing events are reproducibly associated with Alzheimer's disease. We also generate a catalog of splicing quantitative trait loci (sQTL) effects: splicing of 3,006 genes is influenced by genetic variation. We report that altered splicing is the mechanism for the effects of the PICALM, CLU and PTK2B susceptibility alleles. Furthermore, we performed a transcriptome-wide association study and identified 21 genes with significant associations with Alzheimer's disease, many of which are found in known loci, whereas 8 are in novel loci. These results highlight the convergence of old and new genes associated with Alzheimer's disease in autophagy-lysosomal-related pathways. Overall, this study of the transcriptome of the aging brain provides evidence that dysregulation of mRNA splicing is a feature of Alzheimer's disease and is, in some cases, genetically driven.

Year of Publication
2018
Journal
Nat Genet
Volume
50
Issue
11
Pages
1584-1592
Date Published
2018 11
ISSN
1546-1718
DOI
10.1038/s41588-018-0238-1
PubMed ID
30297968
PubMed Central ID
PMC6354244
Links
Grant list
U01 AG046152 / AG / NIA NIH HHS / United States
R01 AG054005 / AG / NIA NIH HHS / United States
R37 MH057881 / MH / NIMH NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
S10 OD018522 / OD / NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
P50 MH084053 / MH / NIMH NIH HHS / United States
HHSN271201300031C / DA / NIDA NIH HHS / United States
P50 MH066392 / MH / NIMH NIH HHS / United States
R01 MH080405 / MH / NIMH NIH HHS / United States
R01 MH075916 / MH / NIMH NIH HHS / United States
R56 AG055824 / AG / NIA NIH HHS / United States
R01 MH097276 / MH / NIMH NIH HHS / United States
P01 AG002219 / AG / NIA NIH HHS / United States
R01 MH093725 / MH / NIMH NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
R01 AG036836 / AG / NIA NIH HHS / United States
R01 MH085542 / MH / NIMH NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States