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PMID: 30297968 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature genetics ·Vol. 50 ·No. 11 ·2018-00-00 ·Pages 1584-1592

Raj T, Li YI, Wong G, Humphrey J, Wang M, Ramdhani S, Wang YC, Ng B, Gupta I, Haroutunian V, Schadt EE, Young-Pearse T, Mostafavi S, Zhang B, Sklar P, Bennett DA, De Jager PL

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.

MeSH Terms
Aged Aged, 80 and over Aging/genetics,metabolism Alternative Splicing/genetics Alzheimer Disease/genetics,metabolism,pathology Brain/metabolism Chromosome Mapping/methods Cohort Studies Female Gene Expression Profiling/methods Genetic Predisposition to Disease Genome-Wide Association Study Humans Male Quantitative Trait Loci/genetics RNA Splicing/genetics Systems Biology/methods Systems Integration Transcriptome/genetics
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Raj Towfique ORCID
Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected]. | Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
Li Yang I ORCID
Section of Genetic Medicine, University of Chicago, Chicago, IL, USA.
Wong Garrett
Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Humphrey Jack ORCID
Genetics Institute, University College London, London, UK. | Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK.
Wang Minghui ORCID
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ramdhani Satesh
Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Wang Ying-Chih
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ng Bernard
Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada. | Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Gupta Ishaan ORCID
Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Haroutunian Vahram ORCID
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | James J. Peters VA Medical Center, New York, NY, USA.
Schadt Eric E ORCID
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Young-Pearse Tracy
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Mostafavi Sara
Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada. | Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Zhang Bin
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Sklar Pamela
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Bennett David A
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
De Jager Philip L ORCID
Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA. [email protected]. | The Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/s41588-018-0238-1
Email
[email protected]
[email protected]
Published
2018-00-00
Epub
2018-00-08
Pages
1584-1592
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC6354244
Subset
IM
Grants
NIA NIH HHS · U01 AG046152 · United States
NIA NIH HHS · R01 AG054005 · United States
NIMH NIH HHS · R37 MH057881 · United States
NIMH NIH HHS · R01 MH075916 · United States
NIA NIH HHS · R01 AG017917 · United States
NIH HHS · S10 OD018522 · United States
NIA NIH HHS · P30 AG010161 · United States
NIMH NIH HHS · P50 MH084053 · United States
NIDA NIH HHS · HHSN271201300031C · United States
NIMH NIH HHS · P50 MH066392 · United States
NIMH NIH HHS · R01 MH080405 · United States
NIMH NIH HHS · R01 MH097276 · United States
NIA NIH HHS · P01 AG002219 · United States
NIMH NIH HHS · R01 MH093725 · United States
NIA NIH HHS · P50 AG005138 · United States
NIA NIH HHS · R01 AG036836 · United States
NIMH NIH HHS · R01 MH085542 · United States
NIA NIH HHS · R01 AG015819 · United States
Corrections
CommentIn
PMID: 30341439
External Links
PubMed source DOI: 10.1038/s41588-018-0238-1 PMC Full Text View journal details
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