TY - JOUR
T1 - Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene
AU - van Blitterswijk, Marka
AU - Mullen, Bianca
AU - Wojtas, Aleksandra
AU - Heckman, Michael G.
AU - Diehl, Nancy N.
AU - Baker, Matthew C.
AU - DeJesus-Hernandez, Mariely
AU - Brown, Patricia H.
AU - Murray, Melissa E.
AU - Hsiung, Ging Yuek R.
AU - Stewart, Heather
AU - Karydas, Anna M.
AU - Finger, Elizabeth
AU - Kertesz, Andrew
AU - Bigio, Eileen H.
AU - Weintraub, Sandra
AU - Mesulam, Marsel
AU - Hatanpaa, Kimmo J.
AU - White, Charles L.
AU - Neumann, Manuela
AU - Strong, Michael J.
AU - Beach, Thomas G.
AU - Wszolek, Zbigniew K.
AU - Lippa, Carol
AU - Caselli, Richard
AU - Petrucelli, Leonard
AU - Josephs, Keith A.
AU - Parisi, Joseph E.
AU - Knopman, David S.
AU - Petersen, Ronald C.
AU - Mackenzie, Ian R.
AU - Seeley, William W.
AU - Grinberg, Lea T.
AU - Miller, Bruce L.
AU - Boylan, Kevin B.
AU - Graff-Radford, Neill R.
AU - Boeve, Bradley F.
AU - Dickson, Dennis W.
AU - Rademakers, Rosa
N1 - Funding Information:
This work was supported by NIH grants R01 NS080882, R01 NS065782, R01 NS076471, R01 AG026251, P01 AG017586, P50 NS072187, P50 AG016574, P30 AG013854, P30 AG012300, P30 AG019610, U01 AG006786, the ALS Therapy Alliance, and the Consortium for Frontotemporal Dementia Research. Data collection at University of British Columbia is supported by CIHR grant #179009. Dr. Van Blitterswijk is supported by the Milton Safenowitz Post-Doctoral Fellowship for ALS research from the ALS Association.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
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U2 - 10.1186/1750-1326-9-38
DO - 10.1186/1750-1326-9-38
M3 - Article
C2 - 25239657
AN - SCOPUS:85005916169
SN - 1750-1326
VL - 9
SP - 38
JO - Molecular neurodegeneration
JF - Molecular neurodegeneration
ER -