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 John Caselli, Leonard Petrucelli, Keith Anthony Josephs, Joseph E Parisi, David S Knopman, Ronald Carl 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 V Rademakers

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)38
Number of pages1
JournalMolecular Neurodegeneration
Volume9
DOIs
StatePublished - 2014

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Frontotemporal Dementia
Motor Neuron Disease
Chromosomes, Human, Pair 9
Open Reading Frames
Age of Onset
Genes
Inborn Genetic Diseases
Survival
Proteolysis
Antioxidants
Alleles
RNA
Mutation
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene. / Van Blitterswijk, Marka; Mullen, Bianca; Wojtas, Aleksandra; Heckman, Michael G.; Diehl, Nancy N.; Baker, Matthew C.; DeJesus-Hernandez, Mariely; Brown, Patricia H.; Murray, Melissa E; Hsiung, Ging Yuek R; Stewart, Heather; Karydas, Anna M.; Finger, Elizabeth; Kertesz, Andrew; Bigio, Eileen H.; Weintraub, Sandra; Mesulam, Marsel; Hatanpaa, Kimmo J.; White, Charles L.; Neumann, Manuela; Strong, Michael J.; Beach, Thomas G.; Wszolek, Zbigniew K; Lippa, Carol; Caselli, Richard John; Petrucelli, Leonard; Josephs, Keith Anthony; Parisi, Joseph E; Knopman, David S; Petersen, Ronald Carl; Mackenzie, Ian R.; Seeley, William W.; Grinberg, Lea T.; Miller, Bruce L.; Boylan, Kevin B.; Graff Radford, Neill R; Boeve, Bradley F; Dickson, Dennis W; Rademakers, Rosa V.

In: Molecular Neurodegeneration, Vol. 9, 2014, p. 38.

Research output: Contribution to journalArticle

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, RJ, 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, RV 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
Van Blitterswijk, Marka ; Mullen, Bianca ; Wojtas, Aleksandra ; Heckman, Michael G. ; Diehl, Nancy N. ; Baker, Matthew C. ; DeJesus-Hernandez, Mariely ; Brown, Patricia H. ; Murray, Melissa E ; Hsiung, Ging Yuek R ; Stewart, Heather ; Karydas, Anna M. ; Finger, Elizabeth ; Kertesz, Andrew ; Bigio, Eileen H. ; Weintraub, Sandra ; Mesulam, Marsel ; Hatanpaa, Kimmo J. ; White, Charles L. ; Neumann, Manuela ; Strong, Michael J. ; Beach, Thomas G. ; Wszolek, Zbigniew K ; Lippa, Carol ; Caselli, Richard John ; Petrucelli, Leonard ; Josephs, Keith Anthony ; Parisi, Joseph E ; Knopman, David S ; Petersen, Ronald Carl ; Mackenzie, Ian R. ; Seeley, William W. ; Grinberg, Lea T. ; Miller, Bruce L. ; Boylan, Kevin B. ; Graff Radford, Neill R ; Boeve, Bradley F ; Dickson, Dennis W ; Rademakers, Rosa V. / Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene. In: Molecular Neurodegeneration. 2014 ; Vol. 9. pp. 38.
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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 Caselli, {Richard John} and Leonard Petrucelli and Josephs, {Keith Anthony} and Parisi, {Joseph E} and Knopman, {David S} and Petersen, {Ronald Carl} 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 Rademakers, {Rosa V}",
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language = "English (US)",
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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 John

AU - Petrucelli, Leonard

AU - Josephs, Keith Anthony

AU - Parisi, Joseph E

AU - Knopman, David S

AU - Petersen, Ronald Carl

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 V

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

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