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.

在这里，我们对衰老人脑中调节基因共表达模块表达的变体进行了全基因组筛选；我们在TMEM106B和RBFOX1位点中发现并复制了此类变异。已知TMEM106B单倍型会影响 TAR DNA 结合蛋白 43 kDa (TDP-43) 蛋白病的积累，并且该单倍型的大规模转录组效应包括溶酶体基因的失调和突触基因剪接的改变，这些也见于TDP-43 蛋白病的病理生理学。此外，另一个 TDP-43 蛋白病易感基因GRN附近的一个变体显示出与TMEM106B单倍型一致的效应。利用来自同一参与者的神经病理学数据，我们还表明TMEM106B和APOE-淀粉样蛋白-β 效应会共同改变髓鞘形成和溶酶体基因表达，从而促进 TDP-43 积累。这些结果推进了我们对TMEM106B TDP-43 风险单倍型的机制理解，并揭示了介导APOE-淀粉样蛋白-β 和TMEM106B对老年人 TDP-43 聚集的聚合效应的转录程序。