Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) 
have recently been linked to frontotemporal lobar degeneration (FTLD) and 
amyotrophic lateral sclerosis, and may be the most common genetic cause of both 
neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the 
most common neuropathological subtype of FTLD, characterized by inclusions of 
TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that 
TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) 
mutations, with the major (risk) allele of rs1990622 associating with earlier 
age at onset of disease. Here, we report that rs1990622 genotype affects age at 
death in a single-site discovery cohort of FTLD patients with C9orf72 expansions 
(n = 14), with the major allele correlated with later age at death (p = 0.024). 
We replicate this modifier effect in a 30-site international neuropathological 
cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that 
the major allele associates with later age at death (p = 0.016), as well as 
later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect 
age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or 
C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 
expansions. Intriguingly, the genotype that confers increased risk for 
developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later 
age at onset and death in C9orf72 expansion carriers, providing an example of 
sign epistasis in human neurodegenerative disease.