PNNL

Abstract

Genetic variants that control distant gene expression are highly relevant for disease mechanisms but remain poorly charaterized. Here, leveraging the modular structure of gene coexpression in the aging human brain, we performed genome-wide association studies of gene coexpression modules and identified TMEM106B and RBFOX1 as module quantitative trait loci (modQTLs). The TMEM106B modQTL is a known risk locus of neurodegenerative TDP-43 proteinopathy and has a large-scale dominant transcriptomic effect including lysosomal and splicing dysregulation, recapitulating TDP-43 pathophysiology. Further, a locus in another TDP-43 proteinopathy risk gene, GRN, shows similar transcriptomic effects. TMEM106B and APOE/amyloid-ß converge on altered myelination/lysosomal gene expression, and jointly promote limbic-predominant age-related TDP-43 encephalopathy neuropathological change. Thus, genetic architecture of distant gene expression in the aging human brain elucidates TDP-43 proteinopathy pathophysiology.