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

Raj, Towfique; Li, Yang; Wong, Garrett; Humphrey, Jack; Wang, Minghui; Ramdhani, Satesh; Wang, Ying-Chih; Ng, Bernard; Gupta, Ishaan; Haroutunian, Vahram; Schadt, Eric E.; Young‐Pearse, Tracy L.; Mostafavi, Sara; Zhang, Bin; Sklar, Pamela; Bennett, David A.; Jager, Philip L. De

doi:10.1038/s41588-018-0238-1

Cited by 349 publications

(346 citation statements)

References 67 publications

(111 reference statements)

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“…After confirming that each mutant was expressed at similar levels to the WT TDP-43 ( Fig. 5B), we next examined their ability to rescue the expression levels/splicing of POLDIP3, PFKP [a previously characterized TDP-43 target gene whose splicing is altered in the elderly human brain (Ling et al, 2015;Raj et al, 2018)], and NUP188. Interestingly, even most TDP-43 mutants rescued the POLDIP, PFKP and Nup188 phenotypes, there were also specific instances where the rescue did not occur (Fig.…”

Section: Disease Causing Tdp-43 Mutants Rescue Ko Phenotypes But Alsomentioning

confidence: 87%

Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis

Roczniak-Ferguson

Ferguson

2019

Preprint

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TDP-43 is an RNA-binding protein that forms cytoplasmic aggregates in multiple neurodegenerative diseases. Although the loss of normal TDP-43 functions likely contributes to disease pathogenesis, the cell biological consequences of human TDP-43 depletion are not well understood. We therefore generated human TDP-43 knockout cells and subjected them to parallel cell biological and transcriptomic analyses. These efforts yielded three important discoveries. First, complete loss of TDP-43 resulted in widespread morphological defects related to multiple organelles including: Golgi, endosomes, lysosomes, mitochondria and the nuclear envelope. Second, we identified a new role for TDP-43 in controlling mRNA splicing of Nup188 (nuclear pore protein). Third, analysis of multiple amyotrophic lateral sclerosis (ALS) causing TDP-43 mutations revealed a broad ability to support splicing of TDP-43 target genes. However, as some TDP-43 disease causing mutants failed to support the regulation of specific target transcripts, our results raise the possibility of mutation-specific loss-of-function contributions to disease pathology.

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Section: Disease Causing Tdp-43 Mutants Rescue Ko Phenotypes But Alsomentioning

confidence: 87%

Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis

Roczniak-Ferguson

Ferguson

2019

Preprint

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“…Multiple recent studies have suggested that functional DNA regions in liver and myeloid cells are strongly enriched for LOAD heritability 35,41,42 . It has also been suggested that alternative splicing may be a mechanism for many risk loci of LOAD 43 . Therefore, in addition to 44 tissues from GTEx, we also incorporated liver eQTL from STARNET and both eQTL and splicing (s)QTL data in three immune cell types (i.e.…”

Section: Utmost Identifies Novel Risk Genes For Alzheimer's Diseasementioning

confidence: 99%

A statistical framework for cross-tissue transcriptome-wide association analysis

et al. 2018

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Transcriptome-wide association analysis is a powerful approach to studying the genetic architecture of complex traits. A key component of this approach is to build a model to impute gene expression levels from genotypes using samples with matched genotypes and gene expression data in a given tissue. However, it is challenging to develop robust and accurate imputation models with a limited sample size for any single tissue. Here, we first introduce a multi-task learning method to jointly impute gene expression in 44 human tissues. Compared with single-tissue methods, our approach achieved an average 39% improvement in imputation accuracy and generated effective imputation models for an average 120% more genes. We then describe a summary statistic-based testing framework that combines multiple single-tissue associations into a powerful metric to quantify the overall gene-trait association. We applied our method, called UTMOST, to multiple genome wide association results and demonstrate its advantages over single-tissue strategies.

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“…suggesting that most of regulation loss was not related to decreased expression of TF genes. We further explored the transcript isoform usage of undifferentially expressed regulators using RNA-seq data [31]. However, we failed to find a strong switch in isoform usage, especially for the abundantly expressed isoforms.…”

Section: Regulation Lossmentioning

confidence: 98%

Accumulated degeneration of transcriptional regulation contributes to disease development and detrimental clinical outcomes of Alzheimer’s disease

Meng

Yuan

et al. 2019

Preprint

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Alzheimer's disease (AD) is extremely complex for both causal mechanism and clinical manifestation, requiring efforts to uncover its diversity and the corresponding mechanisms. Here, we applied a modelling analysis to investigate the regulation divergence among a large-scale cohort of AD patients. We found that transcription regulation tended to get degenerated in AD patients, which contributed to disease development and the detrimental clinical outcomes, mainly by disrupting protein degradation, neuroinflammation, mitochondrial and synaptic functions. To measure the accumulated effects, we came up with a new concept, regulation loss burden, which better correlated with AD related clinical manifestations and the ageing process. The epigenetic studies to multiple active regulation marks also supported a tendency of regulation loss in AD patients. Our finding can lead to a unified model as AD causal mechanism, where AD and its diversity are contributed by accumulated degeneration of transcriptional regulation.The significance of this study is that: (1) it is the first system biology investigation to transcription regulation divergence among AD patients; (2) we observed an accumulated degeneration of transcription regulation, which well correlates with detrimental clinical outcomes; (3) transcriptional degeneration also contributes to the ageing process, where its correlation with ages is up to 0.78. IntroductionAlzheimer's disease (AD) is a complex chronic neurodegenerative disease that has been intensively studied for decades. However, its causal mechanismd remain elusive [1]. More attentions have been focused on the visible neuropathological features, especially the amyloid plaques and neurofibrillary tangles. Amyloid plaques are composed of depositions of insoluble and densely packed amyloid beta (A ) protein whereas neurofibrillary tangles are composed of aggregations of hyperphosphorylated tau protein [2]. Early-onset AD studies in rare families led to the discovery of three genes, amyloid precursor protein, presenilin 1, and presenilin 2 that demonstrated the causal effects of A in the AD progression [3]. However, this is challenged 1 by the observation that some patients with substantial accumulations of plaques have no cognitive impairment [4] and that drugs targeting A all failed in clinical studies [5]. Although neurofibrillary tangles have a stronger correlation with the decline of cognitive ability and have drawn more attentions recently [6,7], strong or direct evidence linking neurofibrillary tangles to AD is still lacking [8].Integrated systematic approaches, especially coexpression regulatory network analysis, have advanced our understanding of AD in different ways [9,10,11]. In such studies, biological networks are constructed using gene-expression data to identify the gene modules related to AD genesis and development by integrating quantitative evaluation into both AD neuropathology and cognitive ability decline. In our previous work, we studied transcriptional dysregulation between AD patients an...

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

Cited by 349 publications

References 67 publications

Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis

Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis

A statistical framework for cross-tissue transcriptome-wide association analysis

Accumulated degeneration of transcriptional regulation contributes to disease development and detrimental clinical outcomes of Alzheimer’s disease

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