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Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia

Bonham, Luke W.; , ; LANDQVIST WALDÖ, MARIA LU ; Nilsson, Karin LU ; Nilsson, Christer LU and Singleton, A. B. (2019) In Scientific Reports 9(1).
Abstract
The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar... (More)
The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration. © 2019, The Author(s). (Less)
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Scientific Reports
volume
9
issue
1
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Nature Publishing Group
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  • scopus:85069717816
ISSN
2045-2322
DOI
10.1038/s41598-019-46415-1
language
English
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yes
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9bd3d9b7-b1a1-4338-a80c-2722d4fd63ad
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https://www.scopus.com/inward/record.uri?eid=2-s2.0-85069717816&doi=10.1038%2fs41598-019-46415-1&partnerID=40&md5=9c44929bf505d5b3276a6af6ac1b0983
date added to LUP
2019-08-30 14:11:18
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2019-09-01 06:26:36
@article{9bd3d9b7-b1a1-4338-a80c-2722d4fd63ad,
  abstract     = {The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration. © 2019, The Author(s).},
  articleno    = {10854 },
  author       = {Bonham, Luke W. and ,  and LANDQVIST WALDÖ, MARIA and Nilsson, Karin and Nilsson, Christer and Singleton, A. B.},
  issn         = {2045-2322},
  language     = {eng},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia},
  url          = {http://dx.doi.org/10.1038/s41598-019-46415-1},
  volume       = {9},
  year         = {2019},
}