TMEM106B is a Genetic Modifier of Frontotemporal Lobar Degeneration with C9orf72 Hexanucleotide Repeat Expansions (I5-1.008)

OBJECTIVE: To evaluate TMEM106B as a genetic modifier in C9orf72-associated frontotemporal lobar degeneration. BACKGROUND: Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), 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 43kDa (FTLD-TDP). DESIGN/METHODS: Discovery cohort-Replication cohort design to investigate the influence of TMEM106B genotype on age at onset and age at death for FTLD-TDP associated with C9orf72 expansions. RESULTS: We report that TMEM106B rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n=14), with the minor allele correlated with earlier 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 minor allele associates with earlier age at death (p=0.016), as well as earlier age at onset (p=0.019). Indeed, in our international replication cohort, with each additional minor allele at rs1990622, patients had a decrease of >3 years in age at death and age at FTLD onset. In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. CONCLUSIONS: TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers decreased risk for developing FTLD-TDP (minor, or C, allele of rs1990622) is associated with earlier age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.