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.

Original languageEnglish
Article number10854
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

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Primary Progressive Aphasia
Gene Regulatory Networks
Semantics
Cell Death
RNA
Frontotemporal Lobar Degeneration
Genetic Phenomena
Protein Interaction Maps
Proteins
Genome-Wide Association Study
Neurodegenerative Diseases
Computer Simulation
Sample Size
Genes
Statistical Factor Analysis

ASJC Scopus subject areas

  • General

Cite this

Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia. / International FTD-Genomics Consortium (IFGC) .

In: Scientific Reports, Vol. 9, No. 1, 10854, 01.12.2019.

Research output: Contribution to journalArticle

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title = "Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia",
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.",
author = "{International FTD-Genomics Consortium (IFGC)} and Bonham, {Luke W.} and Steele, {Natasha Z.R.} and Karch, {Celeste M.} and Iris Broce and Geier, {Ethan G.} and Wen, {Natalie L.} and Parastoo Momeni and John Hardy and Miller, {Zachary A.} and Gorno-Tempini, {Maria Luisa} and Hess, {Christopher P.} and Patrick Lewis and Miller, {Bruce L.} and Seeley, {William W.} and Claudia Manzoni and Desikan, {Rahul S.} and Baranzini, {Sergio E.} and Raffaele Ferrari and Yokoyama, {Jennifer S.} and Hernandez, {D. G.} and Nalls, {M. A.} and Rohrer, {J. D.} and A. Ramasamy and Kwok, {J. B.J.} and C. Dobson-Stone and Schofield, {P. R.} and Halliday, {G. M.} and Hodges, {J. R.} and O. Piguet and L. Bartley and B. Borroni and L. Benussi and G. Binetti and R. Ghidoni and G. Forloni and D. Albani and D. Galimberti and C. Fenoglio and M. Serpente and E. Scarpini and G. Rossi and F. Tagliavini and G. Giaccone and Cappa, {S. F.} and S. Sorbi and L. Bernardi and M. Gallo and V. Novelli and Puca, {A. A.} and M. Franceschi",
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AU - International FTD-Genomics Consortium (IFGC)

AU - Bonham, Luke W.

AU - Steele, Natasha Z.R.

AU - Karch, Celeste M.

AU - Broce, Iris

AU - Geier, Ethan G.

AU - Wen, Natalie L.

AU - Momeni, Parastoo

AU - Hardy, John

AU - Miller, Zachary A.

AU - Gorno-Tempini, Maria Luisa

AU - Hess, Christopher P.

AU - Lewis, Patrick

AU - Miller, Bruce L.

AU - Seeley, William W.

AU - Manzoni, Claudia

AU - Desikan, Rahul S.

AU - Baranzini, Sergio E.

AU - Ferrari, Raffaele

AU - Yokoyama, Jennifer S.

AU - Hernandez, D. G.

AU - Nalls, M. A.

AU - Rohrer, J. D.

AU - Ramasamy, A.

AU - Kwok, J. B.J.

AU - Dobson-Stone, C.

AU - Schofield, P. R.

AU - Halliday, G. M.

AU - Hodges, J. R.

AU - Piguet, O.

AU - Bartley, L.

AU - Borroni, B.

AU - Benussi, L.

AU - Binetti, G.

AU - Ghidoni, R.

AU - Forloni, G.

AU - Albani, D.

AU - Galimberti, D.

AU - Fenoglio, C.

AU - Serpente, M.

AU - Scarpini, E.

AU - Rossi, G.

AU - Tagliavini, F.

AU - Giaccone, G.

AU - Cappa, S. F.

AU - Sorbi, S.

AU - Bernardi, L.

AU - Gallo, M.

AU - Novelli, V.

AU - Puca, A. A.

AU - Franceschi, M.

PY - 2019/12/1

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N2 - 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.

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