Genetics of Gene Expression in the Aging Human Brain Reveal TDP-43 Proteinopathy Pathophysiology

Hyun Sik Yang, Charles C. White, Hans Ulrich Klein, Lei Yu, Christopher Gaiteri, Yiyi Ma, Daniel Felsky, Sara Mostafavi, Vladislav A. Petyuk, Reisa A. Sperling, Nilüfer Ertekin-Taner, Julie A. Schneider, David A. Bennett, Philip L. De Jager

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Here, we perform a genome-wide screen for variants that regulate the expression of gene co-expression modules in the aging human brain; we discover and replicate such variants in the TMEM106B and RBFOX1 loci. The TMEM106B haplotype is known to influence the accumulation of TAR DNA-binding protein 43 kDa (TDP-43) proteinopathy, and the haplotype's large-scale transcriptomic effects include the dysregulation of lysosomal genes and alterations in synaptic gene splicing that are also seen in the pathophysiology of TDP-43 proteinopathy. Further, a variant near GRN, another TDP-43 proteinopathy susceptibility gene, shows concordant effects with the TMEM106B haplotype. Leveraging neuropathology data from the same participants, we also show that TMEM106B and APOE-amyloid-β effects converge to alter myelination and lysosomal gene expression, which then contributes to TDP-43 accumulation. These results advance our mechanistic understanding of the TMEM106B TDP-43 risk haplotype and uncover a transcriptional program that mediates the converging effects of APOE-amyloid-β and TMEM106B on TDP-43 aggregation in older adults. Yang et al. perform a genome-wide screen of regulators of gene co-expression modules and identify TMEM106B and RBFOX1 as key aging human brain transcriptome regulators. Furthermore, TMEM106B and APOE-amyloid-β effects converged on a transcriptional program that mediates TDP-43 aggregation, revealing a key pathogenic link between Alzheimer's disease and TDP-43 proteinopathy.

Original languageEnglish (US)
Pages (from-to)496-508.e6
JournalNeuron
Volume107
Issue number3
DOIs
StatePublished - Aug 5 2020

Keywords

  • Alzheimer's disease
  • Amyloid-β
  • GRN
  • RBFOX1
  • TDP-43
  • TMEM106B
  • co-expression module
  • cognitive resilience
  • eQTL
  • expression quantitative trait loci
  • sQTL
  • splicing quantitative trait loci

ASJC Scopus subject areas

  • Neuroscience(all)

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