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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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).

Detaljer

Författare
  • Luke W. Bonham
  • International FTD-Genomics Consortium (IFGC)
  • MARIA LANDQVIST WALDÖ
  • Karin Nilsson
  • Christer Nilsson
  • A. B. Singleton
Enheter & grupper
Externa organisationer
  • University of California, San Francisco
  • National Institute on Aging, United States
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk genetik
Originalspråkengelska
Artikelnummer10854
TidskriftScientific Reports
Volym9
Utgivningsnummer1
StatusPublished - 2019 jul
PublikationskategoriForskning
Peer review utfördJa