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Background  Hexanucleotide 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.    Results  We 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]).    Conclusions  Variants 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 material  The online version of this article (doi:10.1186/1750-1326-9-38) contains supplementary material, which is available to authorized users.

Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene