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Integrative analyses of splicing in the aging brain: role in susceptibility to Alzheimer’s Disease

View ORCID ProfileTowfique Raj, View ORCID ProfileYang I. Li, Garrett Wong, Satesh Ramdhani, Ying-chih Wang, Bernard Ng, Minghui Wang, Ishaan Gupta, Vahram Haroutunian, Eric E. Schadt, Bin Zhang, Tracy Young-Pearse, View ORCID ProfileSara Mostafavi, View ORCID ProfilePamela Sklar, David Bennett, View ORCID ProfilePhilip L. De Jager
doi: https://doi.org/10.1101/174565
Towfique Raj
1Department of Genetics and Genomic Sciences
2Ronald 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
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  • ORCID record for Towfique Raj
  • For correspondence: towfique.raj@mssm.edu pld2115@cumc.columbia.edu
Yang I. Li
3Department of Genetics, Stanford University, Stanford, CA
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Garrett Wong
1Department of Genetics and Genomic Sciences
2Ronald 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
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Satesh Ramdhani
1Department of Genetics and Genomic Sciences
2Ronald 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
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Ying-chih Wang
1Department of Genetics and Genomic Sciences
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Bernard Ng
4Department of Statistics and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
5Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada
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Minghui Wang
1Department of Genetics and Genomic Sciences
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Ishaan Gupta
2Ronald 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
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Vahram Haroutunian
6Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
7James J. Peters VA Medical Center, 130 West Kingsbridge Road, New York, NY, USA
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Eric E. Schadt
1Department of Genetics and Genomic Sciences
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Bin Zhang
1Department of Genetics and Genomic Sciences
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Tracy Young-Pearse
8Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Sara Mostafavi
4Department of Statistics and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
5Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada
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Pamela Sklar
1Department of Genetics and Genomic Sciences
6Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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David Bennett
9Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, USA
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Philip L. De Jager
10Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, New York, USA
11The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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  • ORCID record for Philip L. De Jager
  • For correspondence: towfique.raj@mssm.edu pld2115@cumc.columbia.edu
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ABSTRACT

We use deep sequencing to identify sources of variation in mRNA splicing in the dorsolateral prefrontal cortex (DLFPC) of 450 subjects from two prospective cohort studies of aging. Hundreds of aberrant pre-mRNA splicing events are reproducibly associated with Alzheimer’s Disease (AD). We also generate a catalog of splicing quantitative trait loci (sQTL) effects in the human cortex: splicing of 3,198 genes is influenced by genetic variation. sQTLs are enriched among those variants influencing DNA methylation and histone acetylation. In assessing known AD loci, we report that altered splicing is the mechanism for the effects of the PICALM, CLU, and PTK2B susceptibility alleles. Further, we leverage our sQTL catalog to identify genes whose aberrant splicing is associated with AD and mediated by genetics. This transcriptome-wide association study identified 21 genes with significant associations, many of which are found in AD GWAS loci, but 8 are in novel AD loci, including FUS, which is a known amyotrophic lateral sclerosis (ALS) gene. This highlights an intriguing shared genetic architecture that is further elaborated by the convergence of old and new AD genes in autophagy-lysosomal-related pathways already implicated in AD and other neurodegenerative diseases. Overall, this study of the aging brain’s transcriptome provides evidence that dysregulation of mRNA splicing is a feature of AD and is, in some genetically-driven cases, causal.

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Posted August 10, 2017.
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Integrative analyses of splicing in the aging brain: role in susceptibility to Alzheimer’s Disease
Towfique Raj, Yang I. Li, Garrett Wong, Satesh Ramdhani, Ying-chih Wang, Bernard Ng, Minghui Wang, Ishaan Gupta, Vahram Haroutunian, Eric E. Schadt, Bin Zhang, Tracy Young-Pearse, Sara Mostafavi, Pamela Sklar, David Bennett, Philip L. De Jager
bioRxiv 174565; doi: https://doi.org/10.1101/174565
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Integrative analyses of splicing in the aging brain: role in susceptibility to Alzheimer’s Disease
Towfique Raj, Yang I. Li, Garrett Wong, Satesh Ramdhani, Ying-chih Wang, Bernard Ng, Minghui Wang, Ishaan Gupta, Vahram Haroutunian, Eric E. Schadt, Bin Zhang, Tracy Young-Pearse, Sara Mostafavi, Pamela Sklar, David Bennett, Philip L. De Jager
bioRxiv 174565; doi: https://doi.org/10.1101/174565

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