Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene

Marka van Blitterswijk; Bianca Mullen; Aleksandra Wojtas; Michael G. Heckman; Nancy N. Diehl; Matthew C. Baker; Mariely DeJesus-Hernandez; Patricia H. Brown; Melissa E. Murray; Ging Yuek R Hsiung; Heather Stewart; Anna M. Karydas; Elizabeth Finger; Andrew Kertesz; Eileen H. Bigio; Sandra Weintraub; Marsel Mesulam; Kimmo J. Hatanpaa; Charles L. White; Manuela Neumann; Michael J. Strong; Thomas G. Beach; Zbigniew K. Wszolek; Carol Lippa; Richard Caselli; Leonard Petrucelli; Keith A. Josephs; Joseph E. Parisi; David S. Knopman; Ronald C. Petersen; Ian R. Mackenzie; William W. Seeley; Lea T. Grinberg; Bruce L. Miller; Kevin B. Boylan; Neill R. Graff-Radford; Bradley F. Boeve; Dennis W. Dickson; Rosa Rademakers

doi:10.1186/1750-1326-9-38

Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene

Marka van Blitterswijk, Bianca Mullen, Aleksandra Wojtas, Michael G. Heckman, Nancy N. Diehl, Matthew C. Baker, Mariely DeJesus-Hernandez, Patricia H. Brown, Melissa E. Murray, Ging Yuek R Hsiung, Heather Stewart, Anna M. Karydas, Elizabeth Finger, Andrew Kertesz, Eileen H. Bigio, Sandra Weintraub, Marsel Mesulam, Kimmo J. Hatanpaa, Charles L. White, Manuela NeumannMichael J. Strong, Thomas G. Beach, Zbigniew K. Wszolek, Carol Lippa, Richard Caselli, Leonard Petrucelli, Keith A. Josephs, Joseph E. Parisi, David S. Knopman, Ronald C. Petersen, Ian R. Mackenzie, William W. Seeley, Lea T. Grinberg, Bruce L. Miller, Kevin B. Boylan, Neill R. Graff-Radford, Bradley F. Boeve, Dennis W. Dickson, Rosa Rademakers

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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.

Original language	English (US)
Pages (from-to)	38
Number of pages	1
Journal	Molecular neurodegeneration
Volume	9
DOIs	https://doi.org/10.1186/1750-1326-9-38
State	Published - 2014

Funding

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.

ASJC Scopus subject areas

Clinical Neurology
Cellular and Molecular Neuroscience
Molecular Biology

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10.1186/1750-1326-9-38

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van Blitterswijk, M., Mullen, B., Wojtas, A., Heckman, M. G., Diehl, N. N., Baker, M. C., DeJesus-Hernandez, M., Brown, P. H., Murray, M. E., Hsiung, G. Y. R., Stewart, H., Karydas, A. M., Finger, E., Kertesz, A., Bigio, E. H., Weintraub, S., Mesulam, M., Hatanpaa, K. J., White, C. L., ... Rademakers, R. (2014). Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene. Molecular neurodegeneration, 9, 38. https://doi.org/10.1186/1750-1326-9-38

@article{c0665c1f3ca347fb9fec5db04813d0ae,

title = "Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene",

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.",

author = "{van Blitterswijk}, Marka and Bianca Mullen and Aleksandra Wojtas and Heckman, {Michael G.} and Diehl, {Nancy N.} and Baker, {Matthew C.} and Mariely DeJesus-Hernandez and Brown, {Patricia H.} and Murray, {Melissa E.} and Hsiung, {Ging Yuek R} and Heather Stewart and Karydas, {Anna M.} and Elizabeth Finger and Andrew Kertesz and Bigio, {Eileen H.} and Sandra Weintraub and Marsel Mesulam and Hatanpaa, {Kimmo J.} and White, {Charles L.} and Manuela Neumann and Strong, {Michael J.} and Beach, {Thomas G.} and Wszolek, {Zbigniew K.} and Carol Lippa and Richard Caselli and Leonard Petrucelli and Josephs, {Keith A.} and Parisi, {Joseph E.} and Knopman, {David S.} and Petersen, {Ronald C.} and Mackenzie, {Ian R.} and Seeley, {William W.} and Grinberg, {Lea T.} and Miller, {Bruce L.} and Boylan, {Kevin B.} and Graff-Radford, {Neill R.} and Boeve, {Bradley F.} and Dickson, {Dennis W.} and Rosa Rademakers",

note = "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.",

year = "2014",

doi = "10.1186/1750-1326-9-38",

language = "English (US)",

volume = "9",

pages = "38",

journal = "Molecular neurodegeneration",

issn = "1750-1326",

publisher = "BioMed Central",

}

van Blitterswijk, M, Mullen, B, Wojtas, A, Heckman, MG, Diehl, NN, Baker, MC, DeJesus-Hernandez, M, Brown, PH, Murray, ME, Hsiung, GYR, Stewart, H, Karydas, AM, Finger, E, Kertesz, A, Bigio, EH , Weintraub, S , Mesulam, M, Hatanpaa, KJ, White, CL, Neumann, M, Strong, MJ, Beach, TG, Wszolek, ZK, Lippa, C, Caselli, R, Petrucelli, L, Josephs, KA, Parisi, JE, Knopman, DS, Petersen, RC, Mackenzie, IR, Seeley, WW, Grinberg, LT, Miller, BL, Boylan, KB, Graff-Radford, NR, Boeve, BF, Dickson, DW & Rademakers, R 2014, 'Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene', Molecular neurodegeneration, vol. 9, pp. 38. https://doi.org/10.1186/1750-1326-9-38

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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UR - http://www.scopus.com/inward/citedby.url?scp=85005916169&partnerID=8YFLogxK

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 -

Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene

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