Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene
详细信息 查看全文
- 作者：Marka van Blitterswijk (1)
Bianca Mullen (1)
Aleksandra Wojtas (1)
Michael G Heckman (2)
Nancy N Diehl (2)
Matthew C Baker (1)
Mariely DeJesus-Hernandez (1)
Patricia H Brown (1)
Melissa E Murray (1)
Ging-Yuek R Hsiung (3)
Heather Stewart (3)
Anna M Karydas (4)
Elizabeth Finger (5)
Andrew Kertesz (5)
Eileen H Bigio (6)
Sandra Weintraub (6)
Marsel Mesulam (6)
Kimmo J Hatanpaa (7)
Charles L White III (7)
Manuela Neumann (8)
Michael J Strong (9)
Thomas G Beach (10)
Zbigniew K Wszolek (11)
Carol Lippa (12)
Richard Caselli (13)
Leonard Petrucelli (1)
Keith A Josephs (14)
Joseph E Parisi (14)
David S Knopman (14)
Ronald C Petersen (14)
Ian R Mackenzie (15)
William W Seeley (4)
Lea T Grinberg (4)
Bruce L Miller (4)
Kevin B Boylan (11)
Neill R Graff-Radford (11)
Bradley F Boeve (14)
Dennis W Dickson (1)
Rosa Rademakers (1)
1. Department of Neuroscience ; Mayo Clinic ; 4500 San Pablo Road ; Jacksonville ; FL ; 32224 ; USA
2. Section of Biostatistics ; Mayo Clinic ; 4500 San Pablo Road ; Jacksonville ; FL ; 32224 ; USA
3. Division of Neurology ; University of British Columbia ; 2211 Wesbrook Mall ; Vancouver ; BC ; V6T 2B5 ; Canada
4. Department of Neurology ; University of California ; 500 Parnassus Ave ; San Francisco ; CA ; 94143 ; USA
5. The University of Western Ontario ; 1151 Richmond St ; London ; ON ; N6A 3 K7 ; Canada
6. Cognitive Neurology and Alzheimer鈥檚 Disease Center ; Northwestern University Feinberg School of Medicine ; 320 East Superior Street ; Chicago ; IL ; 60611 ; USA
7. University of Texas Southwestern Medical Center ; 5323 Harry Hines Blvd ; Dallas ; TX ; 75390 ; USA
8. Department of Neuropathology ; University of T眉bingen and German Center for Neurodegenerative Diseases ; Calwerstr. 3 ; T眉bingen ; 72076 ; Germany
9. Molecular Brain Research Group ; Robarts Research Institute ; 100 Perth Drive ; London ; ON ; N6A 5 K8 ; Canada
10. Banner Sun Health Research Institute ; 10515 W Santa Fe Dr ; Sun City ; AZ ; 85351 ; USA
11. Department of Neurology ; Mayo Clinic ; 4500 San Pablo Road ; Jacksonville ; FL ; 32224 ; USA
12. Department of Neurology ; Drexel University College of Medicine ; 2900 W Queen Ln ; Philadelphia ; PA ; 19129 ; USA
13. Department of Neurology ; Mayo Clinic ; 5777 E Mayo Blvd ; Phoenix ; AZ ; 85054 ; USA
14. Department of Neurology ; Mayo Clinic ; 1216 2nd St SW ; Rochester ; MN ; 55902 ; USA
15. Department of Pathology and Laboratory Medicine ; University of British Columbia ; 2329W Mall ; Vancouver ; BC ; V6T 1Z4 ; Canada - 关键词：C9ORF72 ; Frontotemporal dementia ; Motor neuron disease ; Genetic modifier ; Repeat expansion
- 刊名：Molecular Neurodegeneration
- 出版年：2014
- 出版时间：December 2014
- 年：2014
- 卷：9
- 期：1
- 全文大小：707 KB
- 参考文献：1. Lomen-Hoerth, C, Anderson, T, Miller, B (2002) The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 59: pp. 1077-1079 CrossRef
2. Lomen-Hoerth, C, Murphy, J, Langmore, S, Kramer, JH, Olney, RK, Miller, B (2003) Are amyotrophic lateral sclerosis patients cognitively normal?. Neurology 60: pp. 1094-1097 CrossRef
3. Giordana, MT, Ferrero, P, Grifoni, S, Pellerino, A, Naldi, A, Montuschi, A (2011) Dementia and cognitive impairment in amyotrophic lateral sclerosis: a review. Neurol Sci 32: pp. 9-16 CrossRef
4. Phukan, J, Pender, NP, Hardiman, O (2007) Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol 6: pp. 994-1003 265-X" target="_blank" title="It opens in new window">CrossRef
5. 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 (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314: pp. 130-133 26/science.1134108" target="_blank" title="It opens in new window">CrossRef
6. Mackenzie, IR, Neumann, M, Bigio, EH, Cairns, NJ, Alafuzoff, I, Kril, J, Kovacs, GG, Ghetti, B, Halliday, G, Holm, IE, Ince, PG, Kamphorst, W, Revesz, T, Rozemuller, AJ, Kumar-Singh, S, Akiyama, H, Baborie, A, Spina, S, Dickson, DW, Trojanowski, JQ, Mann, DM (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117: pp. 15-18 CrossRef
7. DeJesus-Hernandez, M, Mackenzie, IR, Boeve, BF, Boxer, AL, Baker, M, Rutherford, NJ, Nicholson, AM, Finch, NA, Flynn, H, Adamson, J, Kouri, N, Wojtas, A, Sengdy, P, Hsiung, GY, Karydas, A, Seeley, WW, Josephs, KA, Coppola, G, Geschwind, DH, Wszolek, ZK, Feldman, H, Knopman, DS, Petersen, RC, Miller, BL, Dickson, DW, Boylan, KB, Graff-Radford, NR, Rademakers, R (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72: pp. 245-256 CrossRef
8. Renton, AE, Majounie, E, Waite, A, Simon-Sanchez, J, Rollinson, S, Gibbs, JR, Schymick, JC, Laaksovirta, H, van Swieten, JC, Myllykangas, L, Kalimo, H, Paetau, A, Abramzon, Y, Remes, AM, Kaganovich, A, Scholz, SW, Duckworth, J, Ding, J, Harmer, DW, Hernandez, DG, Johnson, JO, Mok, K, Ryten, M, Trabzuni, D, Guerreiro, RJ, Orrell, RW, Neal, J, Murray, A, Pearson, J, Jansen, IE (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72: pp. 257-268 CrossRef
9. Majounie, E, Renton, AE, Mok, K, Dopper, EG, Waite, A, Rollinson, S, Chio, A, Restagno, G, Nicolaou, N, Simon-Sanchez, J, van Swieten, JC, Abramzon, Y, Johnson, JO, Sendtner, M, Pamphlett, R, Orrell, RW, Mead, S, Sidle, KC, Houlden, H, Rohrer, JD, Morrison, KE, Pall, H, Talbot, K, Ansorge, O, Hernandez, DG, Arepalli, S, Sabatelli, M, Mora, G, Corbo, M, Giannini, F (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 11: pp. 323-330 CrossRef
10. van Blitterswijk, M, DeJesus-Hernandez, M, Rademakers, R (2012) How do C9ORF72 repeat expansions cause amyotrophic lateral sclerosis and frontotemporal dementia: can we learn from other noncoding repeat expansion disorders?. Curr Opin Neurol 25: pp. 689-700 CrossRef
11. van Blitterswijk, M, Mullen, B, Nicholson, AM, Bieniek, KF, Heckman, MG, Baker, MC, Dejesus-Hernandez, M, Finch, NA, Brown, PH, Murray, ME, Hsiung, GY, Stewart, H, Karydas, AM, Finger, E, Kertesz, A, Bigio, EH, Weintraub, S, Mesulam, M, Hatanpaa, KJ, White Iii, CL, Strong, MJ, Beach, TG, Wszolek, ZK, Lippa, C, Caselli, R, Petrucelli, L, Josephs, KA, Parisi, JE, Knopman, DS, Petersen, RC (2014) TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta Neuropathol 127: pp. 397-406 CrossRef
12. Gallagher, MD, Suh, E, Grossman, M, Elman, L, McCluskey, L, Van Swieten, JC, Al-Sarraj, S, Neumann, M, Gelpi, E, Ghetti, B, Rohrer, JD, Halliday, G, Van Broeckhoven, C, Seilhean, D, Shaw, PJ, Frosch, MP, Alafuzoff, I, Antonell, A, Bogdanovic, N, Brooks, W, Cairns, NJ, Cooper-Knock, J, Cotman, C, Cras, P, Cruts, M, De Deyn, PP, DeCarli, C, Dobson-Stone, C, Engelborghs, S, Fox, N (2014) TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathol 127: pp. 407-418 CrossRef
13. van Blitterswijk, M, Mullen, B, Heckman, MG, Baker, MC, DeJesus-Hernandez, M, Brown, PH, Murray, ME, Hsiung, GY, 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 (2014) Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers. Neurobiol Aging 35: pp. 2421
14. van Blitterswijk, M, DeJesus-Hernandez, M, Niemantsverdriet, E, Murray, ME, Heckman, MG, Diehl, NN, Brown, PH, Baker, MC, Finch, NA, Bauer, PO, Serrano, G, Beach, TG, Josephs, KA, Knopman, DS, Petersen, RC, Boeve, BF, Graff-Radford, NR, Boylan, KB, Petrucelli, L, Dickson, DW, Rademakers, R (2013) Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study. Lancet Neurol 12: pp. 978-988 CrossRef
15. van Blitterswijk, M, Baker, MC, Dejesus-Hernandez, M, Ghidoni, R, Benussi, L, Finger, E, Hsiung, GY, Kelley, BJ, Murray, ME, Rutherford, NJ, Brown, PE, Ravenscroft, T, Mullen, B, Ash, PE, Bieniek, KF, Hatanpaa, KJ, Karydas, A, Wood, EM, Coppola, G, Bigio, EH, Lippa, C, Strong, MJ, Beach, TG, Knopman, DS, Huey, ED, Mesulam, M, Bird, T, White, CL, Kertesz, A, Geschwind, DH (2013) C9ORF72 repeat expansions in cases with previously identified pathogenic mutations. Neurology 81: pp. 1332-1341 CrossRef
16. Wunderley, L, Brownhill, K, Stefani, F, Tabernero, L, Woodman, P (2014) The molecular basis for selective assembly of the UBAP1-containing endosome-specific ESCRT-I complex. J Cell Sci 127: pp. 663-672 CrossRef
17. Stefani, F, Zhang, L, Taylor, S, Donovan, J, Rollinson, S, Doyotte, A, Brownhill, K, Bennion, J, Pickering-Brown, S, Woodman, P (2011) UBAP1 is a component of an endosome-specific ESCRT-I complex that is essential for MVB sorting. Curr Biol 21: pp. 1245-1250 CrossRef
18. Rollinson, S, Rizzu, P, Sikkink, S, Baker, M, Halliwell, N, Snowden, J, Traynor, BJ, Ruano, D, Cairns, N, Rohrer, JD, Mead, S, Collinge, J, Rossor, M, Akay, E, Guerreiro, R, Rademakers, R, Morrison, KE, Pastor, P, Alonso, E, Martinez-Lage, P, Graff-Radford, N, Neary, D, Heutink, P, Mann, DM, Van Swieten, J, Pickering-Brown, SM (2009) Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration. Neurobiol Aging 30: pp. 656-665 CrossRef
19. Rohrer, JD, Mead, S, Omar, R, Poulter, M, Warren, JD, Collinge, J, Rossor, MN (2006) Prion protein (PRNP) genotypes in frontotemporal lobar degeneration syndromes. Ann Neurol 60: pp. 616 CrossRef
20. Li, X, Rowland, LP, Mitsumoto, H, Przedborski, S, Bird, TD, Schellenberg, GD, Peskind, E, Johnson, N, Siddique, T, Mesulam, MM, Weintraub, S, Mastrianni, JA (2005) Prion protein codon 129 genotype prevalence is altered in primary progressive aphasia. Ann Neurol 58: pp. 858-864 CrossRef
21. Moreno, F, Alzualde, A, Camblor, PM, Barandiaran, M, Van Deerlin, VM, Gabilondo, A, Marti Masso, JF, Lopez de Munain, A, Indakoetxea, B (2011) Prion protein codon 129 polymorphism modifies age at onset of frontotemporal dementia with the C.709-1G>A progranulin mutation. Alzheimer Dis Assoc Disord 25: pp. 93-95 CrossRef
22. Chiaverini, N, De Ley, M (2010) Protective effect of metallothionein on oxidative stress-induced DNA damage. Free Radic Res 44: pp. 605-613 CrossRef
23. Morahan, JM, Yu, B, Trent, RJ, Pamphlett, R (2007) Genetic susceptibility to environmental toxicants in ALS. Am J Med Genet B Neuropsychiatr Genet 144B: pp. 885-890 CrossRef
24. Tokuda, E, Okawa, E, Watanabe, S, Ono, S (2014) Overexpression of metallothionein-I, a copper-regulating protein, attenuates intracellular copper dyshomeostasis and extends lifespan in a mouse model of amyotrophic lateral sclerosis caused by mutant superoxide dismutase-1. Hum Mol Genet 23: pp. 1271-1285 CrossRef
25. Kamel, F, Umbach, DM, Hu, H, Munsat, TL, Shefner, JM, Taylor, JA, Sandler, DP (2005) Lead exposure as a risk factor for amyotrophic lateral sclerosis. Neurodegener Dis 2: pp. 195-201 CrossRef
26. Kamel, F, Umbach, DM, Lehman, TA, Park, LP, Munsat, TL, Shefner, JM, Sandler, DP, Hu, H, Taylor, JA (2003) Amyotrophic lateral sclerosis, lead, and genetic susceptibility: polymorphisms in the delta-aminolevulinic acid dehydratase and vitamin D receptor genes. Environ Health Perspect 111: pp. 1335-1339 CrossRef
27. Fang, F, Kwee, LC, Allen, KD, Umbach, DM, Ye, W, Watson, M, Keller, J, Oddone, EZ, Sandler, DP, Schmidt, S, Kamel, F (2010) Association between blood lead and the risk of amyotrophic lateral sclerosis. Am J Epidemiol 171: pp. 1126-1133 CrossRef
28. Rademakers, R, Eriksen, JL, Baker, M, Robinson, T, Ahmed, Z, Lincoln, SJ, Finch, N, Rutherford, NJ, Crook, RJ, Josephs, KA, Boeve, BF, Knopman, DS, Petersen, RC, Parisi, JE, Caselli, RJ, Wszolek, ZK, Uitti, RJ, Feldman, H, Hutton, ML, Mackenzie, IR, Graff-Radford, NR, Dickson, DW (2008) Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Hum Mol Genet 17: pp. 3631-3642 CrossRef
29. Simon-Sanchez, J, Seelaar, H, Bochdanovits, Z, Deeg, DJ, van Swieten, JC, Heutink, P (2009) Variation at GRN 3'-UTR rs5848 is not associated with a risk of frontotemporal lobar degeneration in Dutch population. PLoS One 4: pp. e7494 CrossRef
30. Galimberti, D, Fenoglio, C, Cortini, F, Serpente, M, Venturelli, E, Villa, C, Clerici, F, Marcone, A, Benussi, L, Ghidoni, R, Gallone, S, Scalabrini, D, Restelli, I (2010) Martinelli Boneschi F, Cappa S, Binetti G, Mariani C, Rainero I, Giordana MT, Bresolin N, Scarpini E: GRN variability contributes to sporadic frontotemporal lobar degeneration. J Alzheimers Dis 19: pp. 171-177
31. Rollinson, S, Rohrer, JD, van der Zee, J, Sleegers, K, Mead, S, Engelborghs, S, Collinge, J, De Deyn, PP, Mann, DM, Van Broeckhoven, C, Pickering-Brown, SM (2011) No association of PGRN 3'UTR rs5848 in frontotemporal lobar degeneration. Neurobiol Aging 32: pp. 754-755 CrossRef
32. Pickering-Brown, SM, Rollinson, S, Du Plessis, D, Morrison, KE, Varma, A, Richardson, AM, Neary, D, Snowden, JS, Mann, DM (2008) Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations. Brain 131: pp. 721-731 CrossRef
33. Winkler, GS, Kristjuhan, A, Erdjument-Bromage, H, Tempst, P, Svejstrup, JQ (2002) Elongator is a histone H3 and H4 acetyltransferase important for normal histone acetylation levels in vivo. Proc Natl Acad Sci U S A 99: pp. 3517-3522 CrossRef
34. Winkler, GS, Petrakis, TG, Ethelberg, S, Tokunaga, M, Erdjument-Bromage, H, Tempst, P, Svejstrup, JQ (2001) RNA polymerase II elongator holoenzyme is composed of two discrete subcomplexes. J Biol Chem 276: pp. 32743-32749 CrossRef
35. Belzil, VV, Bauer, PO, Prudencio, M, Gendron, TF, Stetler, CT, Yan, IK, Pregent, L, Daughrity, L, Baker, MC, Rademakers, R, Boylan, K, Patel, TC, Dickson, DW, Petrucelli, L (2013) Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol 126: pp. 895-905 CrossRef
36. Simpson, CL, Lemmens, R, Miskiewicz, K, Broom, WJ, Hansen, VK, van Vught, PW, Landers, JE, Sapp, P, Van Den Bosch, L, Knight, J, Neale, BM, Turner, MR, Veldink, JH, Ophoff, RA, Tripathi, VB, Beleza, A, Shah, MN, Proitsi, P, Van Hoecke, A, Carmeliet, P, Horvitz, HR, Leigh, PN, Shaw, CE, van den Berg, LH, Sham, PC, Powell, JF, Verstreken, P, Brown, RH, Robberecht, W, Al-Chalabi, A (2009) Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Hum Mol Genet 18: pp. 472-481 CrossRef
37. van Blitterswijk, M, Landers, JE (2010) RNA processing pathways in amyotrophic lateral sclerosis. Neurogenetics 11: pp. 275-290 CrossRef
38. Rubino, E, Vacca, A, Govone, F, De Martino, P, Pinessi, L, Rainero, I (2013) Apolipoprotein E polymorphisms in frontotemporal lobar degeneration: a meta-analysis. Alzheimers Dement 9: pp. 706-713 CrossRef
39. van Es, MA, Veldink, JH, Saris, CG, Blauw, HM, van Vught, PW, Birve, A, Lemmens, R, Schelhaas, HJ, Groen, EJ, Huisman, MH, van der Kooi, AJ, de Visser, M, Dahlberg, C, Estrada, K, Rivadeneira, F, Hofman, A, Zwarts, MJ, van Doormaal, PT, Rujescu, D, Strengman, E, Giegling, I, Muglia, P, Tomik, B, Slowik, A, Uitterlinden, AG, Hendrich, C, Waibel, S, Meyer, T, Ludolph, AC, Glass, JD (2009) Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet 41: pp. 1083-1087 CrossRef
40. Diekstra, FP, Saris, CG, van Rheenen, W, Franke, L, Jansen, RC, van Es, MA, van Vught, PW, Blauw, HM, Groen, EJ, Horvath, S, Estrada, K, Rivadeneira, F, Hofman, A, Uitterlinden, AG, Robberecht, W, Andersen, PM, Melki, J, Meininger, V, Hardiman, O, Landers, JE, Brown, RH, Shatunov, A, Shaw, CE, Leigh, PN, Al-Chalabi, A, Ophoff, RA, van den Berg, LH, Veldink, JH (2012) Mapping of gene expression reveals CYP27A1 as a susceptibility gene for sporadic ALS. PLoS One 7: pp. e35333 CrossRef
41. Augustin, I, Rosenmund, C, Sudhof, TC, Brose, N (1999) Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature 400: pp. 457-461 CrossRef
42. Glickman, ME, Rao, SR, Schultz, MR (2014) False discovery rate control is a recommended alternative to Bonferroni-type adjustments in health studies. J Clin Epidemiol 67: pp. 850-857 CrossRef
43. Dudoit, S, van der Laan, MJ, Pollard, KS (2004) Multiple testing. Part I. Single-step procedures for control of general type I error rates. Stat Appl Genet Mol Biol 3: pp. Article13
44. Benjamini, Y, Hochberg, Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 57: pp. 289-300 - 刊物主题：Neurosciences; Neurology; Molecular Medicine;
- 出版者：BioMed Central
- ISSN：1750-1326
文摘
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.