A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers
| Title: | A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers |
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| Authors: | Zhang M; Ferrari R; Tartaglia MC; Keith J; Surace EI; Wolf U; Sato C; Grinberg M; Liang Y; Xi Z; Dupont K; McGoldrick P; Weichert A; McKeever PM; Schneider R; McCorkindale MD; Manzoni C; Rademakers R; Graff-Radford NR; Dickson DW; Parisi JE; Boeve BF; Petersen RC; Miller BL; Seeley WW; van Swieten JC; van Rooij J; Pijnenburg Y; van der Zee J; Van Broeckhoven C; Le Ber I; Van Deerlin V; Suh E; Rohrer JD; Mead S; Graff C; Öijerstedt L; Pickering-Brown S; Rollinson S; Rossi G; Tagliavini F; Brooks WS; Dobson-Stone C; Halliday GM; Hodges JR; Piguet O; Binetti G; Benussi L; Ghidoni R; Nacmias B; Sorbi S; Bruni AC; Galimberti D; Scarpini E; Rainero I; Rubino E; Clarimon J; Lleó A; Ruiz A; Hernández I; Pastor P; Diez-Fairen M; Borroni B; Pasquier F; Deramecourt V; Lebouvier T; Perneczky R; Diehl-Schmid J; Grafman J; Huey ED; Mayeux R; Nalls MA; Hernandez D; Singleton A; Momeni P; Zeng Z; Hardy J; Robertson J; Zinman L; Rogaeva E; International FTD-Genomics Consortium (Ferrari R; Hernandez DG; Ramasamy A; Kwok JBJ; Schofield PR; Bartley L; Thompson E; Boada M; Padovani A; Cruchaga C; Cairns NJ; Forloni G; Albani D; Fenoglio C; Serpente M; Clarimón J; Blesa R; Wald Ouml ML; Nilsson K; Nilsson C; Mackenzie IRA; Hsiung GR; Mann DMA; Morris CM; Attems J; Griffiths TD; McKeith IG; Thomas AJ; Pietrini P; Wassermann EM; Baborie A; Jaros E; Tierney MC; Razquin C; Ortega-Cubero S; Alonso E; Alexopoulos P; Kurz A; Pinessi L; St George-Hyslop P; Giaccone G; Rowe JB; Schlachetzki JCM; Uphill J; Collinge J; Danek A; Van Deerlin VM; Grossman M; Trojanowski JQ; Cappa SF; Leber I; Hannequin D; Golfier V; Vercelletto M; Brice A; Bagnoli S; Piaceri I; Nielsen JE; Hjermind LE; Riemenschneider M; Mayhaus M; Ibach B; Gasparoni G; Pichler S; Gu W; Rossor MN; Fox NC; Warren JD; Grazia Spillantini M; Morris HR; Rizzu P; Heutink P; Snowden JS; Richardson A; Gerhard A; Maletta R; Frangipane F; Cupidi C; Bernardi L; Anfossi M; Gallo M; Elena Conidi M; Smirne N; Baker M; Knopman D; Josephs KA; Karydas AM; Rosen H; Dopper EGP; Seelaar H; Pijnenburg YAL; Scheltens P; Logroscino G; Capozzo R; Novelli V; Puca AA; Franceschi M; Postiglione A; Milan G; Sorrentino P; Kristiansen M; Chiang HH; Rollin A; Kapogiannis D; Ferrucci L; Singleton AB; Momeni P. ) |
| Contributors: | Zhang M, Ferrari R, Tartaglia MC, Keith J, Surace EI, Wolf U, Sato C, Grinberg M, Liang Y, Xi Z, Dupont K, McGoldrick P, Weichert A, McKeever PM, Schneider R, McCorkindale MD, Manzoni C, Rademakers R, Graff-Radford NR, Dickson DW, Parisi JE, Boeve BF, Petersen RC, Miller BL, Seeley WW, van Swieten JC, van Rooij J, Pijnenburg Y, van der Zee J, Van Broeckhoven C, Le Ber I, Van Deerlin V, Suh E, Rohrer JD, Mead S, Graff C, Öijerstedt L, Pickering-Brown S, Rollinson S, Rossi G, Tagliavini F, Brooks WS, Dobson-Stone C, Halliday GM, Hodges JR, Piguet O, Binetti G, Benussi L, Ghidoni R, Nacmias B, Sorbi S, Bruni AC, Galimberti D, Scarpini E, Rainero I, Rubino E, Clarimon J, Lleó A, Ruiz A, Hernández I, Pastor P, Diez-Fairen M, Borroni B, Pasquier F, Deramecourt V, Lebouvier T, Perneczky R, Diehl-Schmid J, Grafman J, Huey ED, Mayeux R, Nalls MA, Hernandez D, Singleton A, Momeni P, Zeng Z, Hardy J, Robertson J, Zinman L, Rogaeva E; International FTD-Genomics Consortium (Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Albani D, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Wald Ouml ML, Nilsson K, Nilsson C, Mackenzie IRA, Hsiung GR, Mann DMA, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wassermann EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky R, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossman M, Trojanowski JQ, van der Zee J, Van Broeckhoven C, Cappa SF, Leber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Grazia Spillantini M, Morris HR, Rizzu P, Heutink P, Snowden JS, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Elena Conidi M, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Petersen RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EGP, Seelaar H, Pijnenburg YAL, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebouvier T, Kapogiannis D, Ferrucci L, Pickering-Brown S, Singleton AB, Hardy J, Momeni P.) |
| Publication Year: | 2018 |
| Collection: | Università degli studi di Torino: AperTo (Archivio Istituzionale ad Accesso Aperto) |
| Description: | The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, ... |
| Document Type: | article in journal/newspaper |
| Language: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/30252044; info:eu-repo/semantics/altIdentifier/wos/WOS:000446548400015; volume:141; issue:10; firstpage:2895; lastpage:2907; numberofpages:13; journal:BRAIN; http://hdl.handle.net/2318/1677461; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85054408708 |
| DOI: | 10.1093/brain/awy238 |
| Availability: | http://hdl.handle.net/2318/1677461; https://doi.org/10.1093/brain/awy238 |
| Rights: | info:eu-repo/semantics/openAccess |
| Accession Number: | edsbas.575C44EA |
| Database: | BASE |