Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation

Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene

Marka van Blitterswijk et al. Mol Neurodegener. .

Abstract

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Associations with age at onset in the overall group of FTD, FTD/MND, and MND probands. Three variants are shown that demonstrate a significant association with age at onset in C9ORF72 expansion carriers (rs7018487:T > G [UBAP1; panel A], rs6052771:A > G [PRNP; panel B], and rs7403881:G > C [MT-Ie; panel C]). In each panel, the mean in the given group is denoted by a solid horizontal line; associations are specified in Table 2 and genotype frequencies in Additional file 1: Table S1.
Figure 2
Figure 2
Variants significantly associated with survival after onset. Six significant associations with survival after onset are presented (rs5848:G > A [GRN; panel A], rs7403881:G > C [MT-Ie; panel B], rs13268953:A > G [ELP3; panel C], the epsilon 4 allele:E4- > E4+ [APOE; panel D], rs12608932:A > C [UNC13A; panel E], and rs1800435G > C [ALAD; panel F]). When three curves are shown (rs5848), zero copies of the minor allele are displayed in black, one copy of the minor allele is displayed in blue, and two copies of the minor allele are displayed in red. If two curves are present (other variants), then the common genotype is shown in black and the rare genotype is shown in blue.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology. 2002;59:1077–1079. doi: 10.1212/WNL.59.7.1077. - DOI - PubMed
    1. Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B. Are amyotrophic lateral sclerosis patients cognitively normal? Neurology. 2003;60:1094–1097. doi: 10.1212/01.WNL.0000055861.95202.8D. - DOI - PubMed
    1. Giordana MT, Ferrero P, Grifoni S, Pellerino A, Naldi A, Montuschi A. Dementia and cognitive impairment in amyotrophic lateral sclerosis: a review. Neurol Sci. 2011;32:9–16. doi: 10.1007/s10072-010-0439-6. - DOI - PubMed
    1. Phukan J, Pender NP, Hardiman O. Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol. 2007;6:994–1003. doi: 10.1016/S1474-4422(07)70265-X. - DOI - PubMed
    1. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314:130–133. doi: 10.1126/science.1134108. - DOI - PubMed

Publication types

MeSH terms