Abstract
BackgroundHexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability.ResultsWe examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, we assessed variants previously implicated in FTD and/or MND; 36 variants were included in our analysis. After adjustment for multiple testing, our analysis revealed three variants significantly associated with age at onset (rs7018487 [UBAP1; p-value = 0.003], rs6052771 [PRNP; p-value = 0.003], and rs7403881 [MT-Ie; p-value = 0.003]), and six variants significantly associated with survival after onset (rs5848 [GRN; p-value = 0.001], rs7403881 [MT-Ie; p-value = 0.001], rs13268953 [ELP3; p-value = 0.003], the epsilon 4 allele [APOE; p-value = 0.004], rs12608932 [UNC13A; p-value = 0.003], and rs1800435 [ALAD; p-value = 0.003]).ConclusionsVariants identified through this study were previously reported to be involved in FTD and/or MND, but we are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic mutation (i.e. C9ORF72 repeat expansion). Although validation of our findings is necessary, these variants highlight the importance of protein degradation, antioxidant defense and RNA-processing pathways, and additionally, they are promising targets for the development of therapeutic strategies and prognostic tests.Electronic supplementary materialThe online version of this article (doi:10.1186/1750-1326-9-38) contains supplementary material, which is available to authorized users.
Highlights
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND)
We investigated a cohort of 330 C9ORF72 expansion carriers and 374 controls for 36 variants known to modify disease risk, age at onset or survival after onset in FTD and/or MND (Table 1; Additional file 1: Table S1)
Under a false discovery rate (FDR) of 10%, none of the variants studied was significantly associated with disease risk, neither in our overall group nor in any of our disease subgroups
Summary
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Frontotemporal dementia (FTD) and motor neuron disease (MND), demonstrate clinical, pathological and genetic overlap. In C9ORF72 expansion carriers, FTD and/or MNDassociated variants that modify disease risk, age at onset or survival after onset have not been studied systematically. For this reason, we conducted a thorough literature search and included 36 known variants in our study. We conducted a thorough literature search and included 36 known variants in our study These variants were investigated in a cohort of 330 C9ORF72 expansion carriers and 374 controls; importantly, we identified eight potential disease modifiers that may aid in explaining the reported phenotypic heterogeneity
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