Frontotemporal dementia is the third most common neurodegenerative disease after AD and Parkinson disease. A study performed in 515 FTLD-TDP cases, including 89 individuals carrying pathogenic mutations in the granulin gene, a known cause of familial FTLD-TDP, identified rs1990622, located 6.9 kilobases downstream of the TMEM106B gene as a genome-wide signal. Interestingly, this signal was stronger among the GRN mutation carriers than in the other FTLD-TDP samples. Based on these findings, Cruchaga et al.,, analyzed if TMEM106B variants modify GRN levels. The found that The risk allele of rs1990622 was associated with a mean decrease of the age at onset of 13 years and with lower plasma GRN levels in both healthy older adults and GRN mutation carriers. Analysis of the HapMap database identified a nonsynonymous single-nucleotide polymorphism rs3173615 in perfect linkage disequilibrium with rs1990622, that my represent the functional variant driving the association. In summary, these results indicate that the association of rs1990622 with age at onset explains, in part, the wide range in the onset of disease among GRN mutation carriers. The rs1990622 or another variant in linkage disequilibrium could act in a manner similar to APOE in Alzheimer disease, increasing risk for disease in the general population and modifying AAO in mutation carriers. Genetic variation in TMEM106B may influence risk for FTLD-TDP by modulating secreted levels of GRN.
Functional Mechanism
Li et al., developed and validated a digital deconvolution algorithm to determine the cell proportions in a bulk RNA-seq experiment. Then, they leveraged this method to identify genes associated with the neuronal proportions in the human cortex. In this study, Cruchaga and his team s demonstrated that the TMEM106B variants, that are associated with lower Frontotemporal dementia risk are also associated with higher neuronal content. They also demonstrated that this association was independent of disease status and that TMEM106B is a general protective factor for neruodegeneration, which opens the doors to novel therapeutical approaches targeting TMEM106B.
