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

Neuron. 2020 Aug 5;107(3):496-508.e6. doi: 10.1016/j.neuron.2020.05.010. Epub 2020 Jun 10.


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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aging / genetics*
  • Aging / psychology
  • Alzheimer Disease / genetics
  • Amyloid beta-Peptides / metabolism
  • Apolipoproteins E / genetics
  • Brain / metabolism*
  • Brain / pathology
  • Cohort Studies
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression Regulation / genetics*
  • Haplotypes
  • Humans
  • Lysosomes
  • Male
  • Membrane Proteins / genetics*
  • Myelin Sheath
  • Nerve Tissue Proteins / genetics*
  • Progranulins / genetics*
  • Quantitative Trait Loci
  • RNA Splicing Factors / genetics*
  • TDP-43 Proteinopathies / genetics*
  • TDP-43 Proteinopathies / psychology


  • Amyloid beta-Peptides
  • Apolipoproteins E
  • DNA-Binding Proteins
  • GRN protein, human
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Progranulins
  • RBFOX1 protein, human
  • RNA Splicing Factors
  • TARDBP protein, human
  • TMEM106B protein, human