Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene

Molecular Neurodegeneration

Rosa Rademakers²  Dennis W Dickson²  Bradley F Boeve⁸  Neill R Graff-Radford^1,10  Kevin B Boylan^1,10  Bruce L Miller⁹  Lea T Grinberg⁹  William W Seeley⁹  Ian R Mackenzie^1,13  Ronald C Petersen⁸  David S Knopman⁸  Joseph E Parisi⁸  Keith A Josephs⁸  Leonard Petrucelli²  Richard Caselli⁴  Carol Lippa^1,14  Zbigniew K Wszolek^1,10  Thomas G Beach³  Michael J Strong¹  Manuela Neumann^1,15  Charles L White^1,12  Kimmo J Hatanpaa^1,12  Marsel Mesulam⁵  Sandra Weintraub⁵  Eileen H Bigio⁵  Andrew Kertesz^1,11  Elizabeth Finger^1,11  Anna M Karydas⁹  Heather Stewart⁶  Ging-Yuek R Hsiung⁶  Melissa E Murray²  Patricia H Brown²  Mariely DeJesus-Hernandez²  Matthew C Baker²  Nancy N Diehl⁷  Michael G Heckman⁷  Aleksandra Wojtas²  Bianca Mullen²  Marka van Blitterswijk² 

[1] Molecular Brain Research Group, Robarts Research Institute, 100 Perth Drive, London, ON N6A 5 K8, Canada;Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA;Banner Sun Health Research Institute, 10515 W Santa Fe Dr, Sun City, AZ 85351, USA;Department of Neurology, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ 85054, USA;Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Chicago, IL 60611, USA;Division of Neurology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada;Section of Biostatistics, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA;Department of Neurology, Mayo Clinic, 1216 2nd St SW, Rochester, MN 55902, USA;Department of Neurology, University of California, 500 Parnassus Ave, San Francisco, CA 94143, USA;Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA;The University of Western Ontario, 1151 Richmond St, London, ON N6A 3 K7, Canada;University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA;Department of Pathology and Laboratory Medicine, University of British Columbia, 2329W Mall, Vancouver, BC V6T 1Z4, Canada;Department of Neurology, Drexel University College of Medicine, 2900 W Queen Ln, Philadelphia, PA 19129, USA;Department of Neuropathology, University of Tübingen and German Center for Neurodegenerative Diseases, Calwerstr. 3, Tübingen 72076, Germany

关键词: Repeat expansion;    Genetic modifier;    Motor neuron disease;    Frontotemporal dementia;    C9ORF72;   

Others  :  1138744
DOI  :  10.1186/1750-1326-9-38

 received in 2014-08-07, accepted in 2014-08-29,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 van Blitterswijk et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Lomen-Hoerth C, Anderson T, Miller B: The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 2002, 59:1077-1079.
• [2]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.
• [3]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.
• [4]Phukan J, Pender NP, Hardiman O: Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol 2007, 6:994-1003.
• [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: Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006, 314:130-133.
• [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: Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 2009, 117:15-18.
• [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: Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011, 72:245-256.
• [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, et al.: A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011, 72:257-268.
• [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, et al.: Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 2012, 11:323-330.
• [10]van Blitterswijk M, DeJesus-Hernandez M, Rademakers R: How do C9ORF72 repeat expansions cause amyotrophic lateral sclerosis and frontotemporal dementia: can we learn from other noncoding repeat expansion disorders? Curr Opin Neurol 2012, 25:689-700.
• [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, et al.: TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta Neuropathol 2014, 127:397-406.
• [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, et al.: TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathol 2014, 127:407-418.
• [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 3rd, 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, et al.: Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers. Neurobiol Aging 2014, 35:2421. e2413–2427
• [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: Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study. Lancet Neurol 2013, 12:978-988.
• [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 3rd, Kertesz A, Geschwind DH, et al.: C9ORF72 repeat expansions in cases with previously identified pathogenic mutations. Neurology 2013, 81:1332-1341.
• [16]Wunderley L, Brownhill K, Stefani F, Tabernero L, Woodman P: The molecular basis for selective assembly of the UBAP1-containing endosome-specific ESCRT-I complex. J Cell Sci 2014, 127:663-672.
• [17]Stefani F, Zhang L, Taylor S, Donovan J, Rollinson S, Doyotte A, Brownhill K, Bennion J, Pickering-Brown S, Woodman P: UBAP1 is a component of an endosome-specific ESCRT-I complex that is essential for MVB sorting. Curr Biol 2011, 21:1245-1250.
• [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: Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration. Neurobiol Aging 2009, 30:656-665.
• [19]Rohrer JD, Mead S, Omar R, Poulter M, Warren JD, Collinge J, Rossor MN: Prion protein (PRNP) genotypes in frontotemporal lobar degeneration syndromes. Ann Neurol 2006, 60:616. author reply 617
• [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: Prion protein codon 129 genotype prevalence is altered in primary progressive aphasia. Ann Neurol 2005, 58:858-864.
• [21]Moreno F, Alzualde A, Camblor PM, Barandiaran M, Van Deerlin VM, Gabilondo A, Marti Masso JF, Lopez de Munain A, Indakoetxea B: Prion protein codon 129 polymorphism modifies age at onset of frontotemporal dementia with the C.709-1G>A progranulin mutation. Alzheimer Dis Assoc Disord 2011, 25:93-95.
• [22]Chiaverini N, De Ley M: Protective effect of metallothionein on oxidative stress-induced DNA damage. Free Radic Res 2010, 44:605-613.
• [23]Morahan JM, Yu B, Trent RJ, Pamphlett R: Genetic susceptibility to environmental toxicants in ALS. Am J Med Genet B Neuropsychiatr Genet 2007, 144B:885-890.
• [24]Tokuda E, Okawa E, Watanabe S, Ono S: 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 2014, 23:1271-1285.
• [25]Kamel F, Umbach DM, Hu H, Munsat TL, Shefner JM, Taylor JA, Sandler DP: Lead exposure as a risk factor for amyotrophic lateral sclerosis. Neurodegener Dis 2005, 2:195-201.
• [26]Kamel F, Umbach DM, Lehman TA, Park LP, Munsat TL, Shefner JM, Sandler DP, Hu H, Taylor JA: Amyotrophic lateral sclerosis, lead, and genetic susceptibility: polymorphisms in the delta-aminolevulinic acid dehydratase and vitamin D receptor genes. Environ Health Perspect 2003, 111:1335-1339.
• [27]Fang F, Kwee LC, Allen KD, Umbach DM, Ye W, Watson M, Keller J, Oddone EZ, Sandler DP, Schmidt S, Kamel F: Association between blood lead and the risk of amyotrophic lateral sclerosis. Am J Epidemiol 2010, 171:1126-1133.
• [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: Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Hum Mol Genet 2008, 17:3631-3642.
• [29]Simon-Sanchez J, Seelaar H, Bochdanovits Z, Deeg DJ, van Swieten JC, Heutink P: Variation at GRN 3'-UTR rs5848 is not associated with a risk of frontotemporal lobar degeneration in Dutch population. PLoS One 2009, 4:e7494.
• [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: 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 2010, 19:171-177.
• [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: No association of PGRN 3'UTR rs5848 in frontotemporal lobar degeneration. Neurobiol Aging 2011, 32:754-755.
• [32]Pickering-Brown SM, Rollinson S, Du Plessis D, Morrison KE, Varma A, Richardson AM, Neary D, Snowden JS, Mann DM: 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 2008, 131:721-731.
• [33]Winkler GS, Kristjuhan A, Erdjument-Bromage H, Tempst P, Svejstrup JQ: Elongator is a histone H3 and H4 acetyltransferase important for normal histone acetylation levels in vivo. Proc Natl Acad Sci U S A 2002, 99:3517-3522.
• [34]Winkler GS, Petrakis TG, Ethelberg S, Tokunaga M, Erdjument-Bromage H, Tempst P, Svejstrup JQ: RNA polymerase II elongator holoenzyme is composed of two discrete subcomplexes. J Biol Chem 2001, 276:32743-32749.
• [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: Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol 2013, 126:895-905.
• [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 Jr, Robberecht W, Al-Chalabi A: Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Hum Mol Genet 2009, 18:472-481.
• [37]van Blitterswijk M, Landers JE: RNA processing pathways in amyotrophic lateral sclerosis. Neurogenetics 2010, 11:275-290.
• [38]Rubino E, Vacca A, Govone F, De Martino P, Pinessi L, Rainero I: Apolipoprotein E polymorphisms in frontotemporal lobar degeneration: a meta-analysis. Alzheimers Dement 2013, 9:706-713.
• [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, et al.: Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet 2009, 41:1083-1087.
• [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 Jr, Shatunov A, Shaw CE, Leigh PN, Al-Chalabi A, Ophoff RA, van den Berg LH, Veldink JH: Mapping of gene expression reveals CYP27A1 as a susceptibility gene for sporadic ALS. PLoS One 2012, 7:e35333.
• [41]Augustin I, Rosenmund C, Sudhof TC, Brose N: Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature 1999, 400:457-461.
• [42]Glickman ME, Rao SR, Schultz MR: False discovery rate control is a recommended alternative to Bonferroni-type adjustments in health studies. J Clin Epidemiol 2014, 67:850-857.
• [43]Dudoit S, van der Laan MJ, Pollard KS: Multiple testing. Part I. Single-step procedures for control of general type I error rates. Stat Appl Genet Mol Biol 2004, 3:Article13.
• [44]Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 1995, 57:289-300.