TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions

Abstract

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.

Fig. 1. TMEM106B genotype influences age at death and age at onset in C9orf72(+) FTLD

All survival analyses were performed in 104 total C9orf72(+) FTLD cases, from the combined discovery and replication cohorts. Of these 104 total cases, 89 had available age-at-death data, and 94 had age-at-onset data. A) Age at death was significantly associated with TMEM106B genotype at rs1990622, the top SNP associated with FTLD-TDP in our prior GWAS. Log rank test for trend two-tailed p=0.046, assuming a codominant model. B) Under a major-allele-dominant model, TMEM106B rs1990622 genotype was even more significantly associated with age at death, with more than twice the risk of death at any given age for CC carriers compared to carriers of one or more T alleles (two-tailed p=0.041, HR=2.039, 95% CI 1.031–4.033). C) Age at onset showed a trend towards association with TMEM106B genotype at rs1990622. Log rank test for trend two-tailed p=0.064, assuming a codominant model. D) Under a major-allele-dominant model, TMEM106B rs1990622 genotype showed a significant association with age at disease onset, with more than twice the risk of disease onset at any given age for CC carriers compared to carriers of one or more T alleles (two-tailed p=0.037, HR=2.022, 95% CI 1.042–3.925)

Fig. 2. TMEM106B genotype does not affect age at death or age at onset for FTLD-TDP without C9orf72 expansions

A) In 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions, TMEM106B genotype at rs1990622 did not affect age at death. B) In 116 FTLD-TDP cases with GRN mutations, we found no significant difference in age at death comparing TT and TC carriers at rs1990622. In this cohort, only one individual had the CC genotype, precluding our ability to evaluate the influence of this genotype. C) Plasma progranulin levels were measured in a convenience subset of 24 C9orf72 expansion carriers by ELISA. Progranulin levels did not differ significantly by TMEM106B rs1990622 genotype, although the TT carriers exhibited significantly less variance in their progranulin levels. Black dots indicate individuals who presented with ALS, while red dots indicate individuals who presented with FTLD.