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

Abstract

Genetic variants that control multiple distant gene expressions are highly relevant for disease mechanisms. Here, in the aging human brain, we perform genome-wide screen of variants that regulate the average expression of each gene co-expression network and identify such variants in TMEM106B and RBFOX1 loci. The TMEM106 Blocus coincides with a known TDP-43 proteinopathy risk haplotype, and shows large-scale transcriptomic effects including lysosomal dysregulation and altered synaptic gene splicing, that capture TDP-43 proteinopathy pathophysiology. Further, a locus in GRN, another TDP-43 proteinopathy risk gene, shows concordant effects with the TMEM106B locus. Leveraging neuropathology data from the same participants, we also show that TMEM106B and APOE/amyloid-β effects converge to alter myelination/lysosomal gene expression, which then contributes to TDP-43 accumulation. These results advance our mechanistic understanding of the TMEM106B TDP-43 risk allele, and uncover a transcriptional program that mediates APOE/amyloid-β and TMEM106B effects on TDP-43 aggregation in older adults.