Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS

E. Taskesen, A. Mishra, S. van der Sluis, R. Ferrari, J. H. Veldink, M. A. van Es, A. B. Smit, D. Posthuma, Y. Pijnenburg*, D. G. Hernandez, M. A. Nalls, J. D. Rohrer, A. Ramasamy, J. B.J. Kwok, C. Dobson-Stone, P. R. Schofield, G. M. Halliday, J. R. Hodges, O. Piguet, L. Bartley & 142 others E. Thompson, E. Haan, I. Hernández, A. Ruiz, M. Boada, B. Borroni, A. Padovani, C. Cruchaga, N. J. Cairns, L. Benussi, G. Binetti, R. Ghidoni, G. Forloni, D. Albani, D. Galimberti, C. Fenoglio, M. Serpente, E. Scarpini, J. Clarimón, A. Lleó, R. Blesa, M. Landqvist Waldö, K. Nilsson, C. Nilsson, I. R.A. Mackenzie, G. Y.R. Hsiung, D. M.A. Mann, Jordan Henry Grafman, C. M. Morris, J. Attems, T. D. Griffiths, I. G. McKeith, A. J. Thomas, P. Pietrini, E. D. Huey, E. M. Wassermann, A. Baborie, E. Jaros, M. C. Tierney, P. Pastor, C. Razquin, S. Ortega-Cubero, E. Alonso, R. Perneczky, J. Diehl-Schmid, P. Alexopoulos, A. Kurz, I. Rainero, E. Rubino, L. Pinessi, E. Rogaeva, P. St George-Hyslop, G. Rossi, F. Tagliavini, G. Giaccone, J. B. Rowe, J. C.M. Schlachetzki, J. Uphill, J. Collinge, S. Mead, A. Danek, V. M. Van Deerlin, M. Grossman, J. Q. Trojanowski, J. van der Zee, C. Van Broeckhoven, S. F. Cappa, I. Leber, D. Hannequin, V. Golfier, M. Vercelletto, A. Brice, B. Nacmias, S. Sorbi, S. Bagnoli, I. Piaceri, J. E. Nielsen, L. E. Hjermind, M. Riemenschneider, M. Mayhaus, B. Ibach, G. Gasparoni, S. Pichler, W. Gu, M. N. Rossor, N. C. Fox, J. D. Warren, M. G. Spillantini, H. R. Morris, P. Rizzu, P. Heutink, J. S. Snowden, S. Rollinson, A. Richardson, A. Gerhard, A. C. Bruni, R. Maletta, F. Frangipane, C. Cupidi, L. Bernardi, M. Anfossi, M. Gallo, M. E. Conidi, N. Smirne, R. Rademakers, M. Baker, D. W. Dickson, N. R. Graff-Radford, R. C. Petersen, D. Knopman, K. A. Josephs, B. F. Boeve, J. E. Parisi, W. W. Seeley, B. L. Miller, A. M. Karydas, H. Rosen, J. C. van Swieten, E. G.P. Dopper, H. Seelaar, P. Scheltens, G. Logroscino, R. Capozzo, V. Novelli, A. A. Puca, M. Franceschi, A. Postiglione, G. Milan, P. Sorrentino, M. Kristiansen, H. H. Chiang, C. Graff, F. Pasquier, A. Rollin, V. Deramecourt, T. Lebouvier, D. Kapogiannis, L. Ferrucci, S. Pickering-Brown, A. B. Singleton, J. Hardy, P. Momeni

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS; n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene (ELP2). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35, and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.

Original languageEnglish (US)
Article number8899
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Frontotemporal Dementia
Genome-Wide Association Study
DNA Methylation
Genes
Frontotemporal Dementia With Motor Neuron Disease
Mutation
Amyotrophic Lateral Sclerosis
Frontal Lobe
Temporal Lobe
Epigenomics
Neurodegenerative Diseases
Cluster Analysis

ASJC Scopus subject areas

  • General

Cite this

Taskesen, E. ; Mishra, A. ; van der Sluis, S. ; Ferrari, R. ; Veldink, J. H. ; van Es, M. A. ; Smit, A. B. ; Posthuma, D. ; Pijnenburg, Y. ; Hernandez, D. G. ; Nalls, M. A. ; Rohrer, J. D. ; Ramasamy, A. ; Kwok, J. B.J. ; Dobson-Stone, C. ; Schofield, P. R. ; Halliday, G. M. ; Hodges, J. R. ; Piguet, O. ; Bartley, L. ; Thompson, E. ; Haan, E. ; Hernández, I. ; Ruiz, A. ; Boada, M. ; Borroni, B. ; Padovani, A. ; Cruchaga, C. ; Cairns, N. J. ; Benussi, L. ; Binetti, G. ; Ghidoni, R. ; Forloni, G. ; Albani, D. ; Galimberti, D. ; Fenoglio, C. ; Serpente, M. ; Scarpini, E. ; Clarimón, J. ; Lleó, A. ; Blesa, R. ; Waldö, M. Landqvist ; Nilsson, K. ; Nilsson, C. ; Mackenzie, I. R.A. ; Hsiung, G. Y.R. ; Mann, D. M.A. ; Grafman, Jordan Henry ; Morris, C. M. ; Attems, J. ; Griffiths, T. D. ; McKeith, I. G. ; Thomas, A. J. ; Pietrini, P. ; Huey, E. D. ; Wassermann, E. M. ; Baborie, A. ; Jaros, E. ; Tierney, M. C. ; 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, J. B. ; Schlachetzki, J. C.M. ; Uphill, J. ; Collinge, J. ; Mead, S. ; Danek, A. ; Van Deerlin, V. M. ; Grossman, M. ; Trojanowski, J. Q. ; van der Zee, J. ; Van Broeckhoven, C. ; Cappa, S. F. ; Leber, I. ; Hannequin, D. ; Golfier, V. ; Vercelletto, M. ; Brice, A. ; Nacmias, B. ; Sorbi, S. ; Bagnoli, S. ; Piaceri, I. ; Nielsen, J. E. ; Hjermind, L. E. ; Riemenschneider, M. ; Mayhaus, M. ; Ibach, B. ; Gasparoni, G. ; Pichler, S. ; Gu, W. ; Rossor, M. N. ; Fox, N. C. ; Warren, J. D. ; Spillantini, M. G. ; Morris, H. R. ; Rizzu, P. ; Heutink, P. ; Snowden, J. S. ; Rollinson, S. ; Richardson, A. ; Gerhard, A. ; Bruni, A. C. ; Maletta, R. ; Frangipane, F. ; Cupidi, C. ; Bernardi, L. ; Anfossi, M. ; Gallo, M. ; Conidi, M. E. ; Smirne, N. ; Rademakers, R. ; Baker, M. ; Dickson, D. W. ; Graff-Radford, N. R. ; Petersen, R. C. ; Knopman, D. ; Josephs, K. A. ; Boeve, B. F. ; Parisi, J. E. ; Seeley, W. W. ; Miller, B. L. ; Karydas, A. M. ; Rosen, H. ; van Swieten, J. C. ; Dopper, E. G.P. ; Seelaar, H. ; Scheltens, P. ; Logroscino, G. ; Capozzo, R. ; Novelli, V. ; Puca, A. A. ; Franceschi, M. ; Postiglione, A. ; Milan, G. ; Sorrentino, P. ; Kristiansen, M. ; Chiang, H. H. ; Graff, C. ; Pasquier, F. ; Rollin, A. ; Deramecourt, V. ; Lebouvier, T. ; Kapogiannis, D. ; Ferrucci, L. ; Pickering-Brown, S. ; Singleton, A. B. ; Hardy, J. ; Momeni, P. / Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS. In: Scientific reports. 2017 ; Vol. 7, No. 1.
@article{6b09cb8da5a1476e86febbbe0cacd30b,
title = "Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS",
abstract = "Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS; n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene (ELP2). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35, and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.",
author = "E. Taskesen and A. Mishra and {van der Sluis}, S. and R. Ferrari and Veldink, {J. H.} and {van Es}, {M. A.} and Smit, {A. B.} and D. Posthuma and Y. Pijnenburg and Hernandez, {D. G.} and Nalls, {M. A.} and Rohrer, {J. D.} and A. Ramasamy and Kwok, {J. B.J.} and C. Dobson-Stone and Schofield, {P. R.} and Halliday, {G. M.} and Hodges, {J. R.} and O. Piguet and L. Bartley and E. Thompson and E. Haan and I. Hern{\'a}ndez and A. Ruiz and M. Boada and B. Borroni and A. Padovani and C. Cruchaga and Cairns, {N. J.} and L. Benussi and G. Binetti and R. Ghidoni and G. Forloni and D. Albani and D. Galimberti and C. Fenoglio and M. Serpente and E. Scarpini and J. Clarim{\'o}n and A. Lle{\'o} and R. Blesa and Wald{\"o}, {M. Landqvist} and K. Nilsson and C. Nilsson and Mackenzie, {I. R.A.} and Hsiung, {G. Y.R.} and Mann, {D. M.A.} and Grafman, {Jordan Henry} and Morris, {C. M.} and J. Attems and Griffiths, {T. D.} and McKeith, {I. G.} and Thomas, {A. J.} and P. Pietrini and Huey, {E. D.} and Wassermann, {E. M.} and A. Baborie and E. Jaros and Tierney, {M. C.} and P. Pastor and C. Razquin and S. Ortega-Cubero and E. Alonso and R. Perneczky and J. Diehl-Schmid and P. Alexopoulos and A. Kurz and I. Rainero and E. Rubino and L. Pinessi and E. Rogaeva and {St George-Hyslop}, P. and G. Rossi and F. Tagliavini and G. Giaccone and Rowe, {J. B.} and Schlachetzki, {J. C.M.} and J. Uphill and J. Collinge and S. Mead and A. Danek and {Van Deerlin}, {V. M.} and M. Grossman and Trojanowski, {J. Q.} and {van der Zee}, J. and {Van Broeckhoven}, C. and Cappa, {S. F.} and I. Leber and D. Hannequin and V. Golfier and M. Vercelletto and A. Brice and B. Nacmias and S. Sorbi and S. Bagnoli and I. Piaceri and Nielsen, {J. E.} and Hjermind, {L. E.} and M. Riemenschneider and M. Mayhaus and B. Ibach and G. Gasparoni and S. Pichler and W. Gu and Rossor, {M. N.} and Fox, {N. C.} and Warren, {J. D.} and Spillantini, {M. G.} and Morris, {H. R.} and P. Rizzu and P. Heutink and Snowden, {J. S.} and S. Rollinson and A. Richardson and A. Gerhard and Bruni, {A. C.} and R. Maletta and F. Frangipane and C. Cupidi and L. Bernardi and M. Anfossi and M. Gallo and Conidi, {M. E.} and N. Smirne and R. Rademakers and M. Baker and Dickson, {D. W.} and Graff-Radford, {N. R.} and Petersen, {R. C.} and D. Knopman and Josephs, {K. A.} and Boeve, {B. F.} and Parisi, {J. E.} and Seeley, {W. W.} and Miller, {B. L.} and Karydas, {A. M.} and H. Rosen and {van Swieten}, {J. C.} and Dopper, {E. G.P.} and H. Seelaar and P. Scheltens and G. Logroscino and R. Capozzo and V. Novelli and Puca, {A. A.} and M. Franceschi and A. Postiglione and G. Milan and P. Sorrentino and M. Kristiansen and Chiang, {H. H.} and C. Graff and F. Pasquier and A. Rollin and V. Deramecourt and T. Lebouvier and D. Kapogiannis and L. Ferrucci and S. Pickering-Brown and Singleton, {A. B.} and J. Hardy and P. Momeni",
year = "2017",
month = "12",
day = "1",
doi = "10.1038/s41598-017-09320-z",
language = "English (US)",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

Taskesen, E, Mishra, A, van der Sluis, S, Ferrari, R, Veldink, JH, van Es, MA, Smit, AB, Posthuma, D, Pijnenburg, Y, Hernandez, DG, Nalls, MA, Rohrer, JD, Ramasamy, A, Kwok, JBJ, Dobson-Stone, C, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Haan, 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, Waldö, ML, Nilsson, K, Nilsson, C, Mackenzie, IRA, Hsiung, GYR, Mann, DMA, Grafman, JH, 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, Spillantini, MG, 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, Conidi, ME, 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, 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 2017, 'Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS', Scientific reports, vol. 7, no. 1, 8899. https://doi.org/10.1038/s41598-017-09320-z

Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS. / Taskesen, E.; Mishra, A.; van der Sluis, S.; Ferrari, R.; Veldink, J. H.; van Es, M. A.; Smit, A. B.; Posthuma, D.; Pijnenburg, Y.; Hernandez, D. G.; Nalls, M. A.; Rohrer, J. D.; Ramasamy, A.; Kwok, J. B.J.; Dobson-Stone, C.; Schofield, P. R.; Halliday, G. M.; Hodges, J. R.; Piguet, O.; Bartley, L.; Thompson, E.; Haan, E.; Hernández, I.; Ruiz, A.; Boada, M.; Borroni, B.; Padovani, A.; Cruchaga, C.; Cairns, N. J.; Benussi, L.; Binetti, G.; Ghidoni, R.; Forloni, G.; Albani, D.; Galimberti, D.; Fenoglio, C.; Serpente, M.; Scarpini, E.; Clarimón, J.; Lleó, A.; Blesa, R.; Waldö, M. Landqvist; Nilsson, K.; Nilsson, C.; Mackenzie, I. R.A.; Hsiung, G. Y.R.; Mann, D. M.A.; Grafman, Jordan Henry; Morris, C. M.; Attems, J.; Griffiths, T. D.; McKeith, I. G.; Thomas, A. J.; Pietrini, P.; Huey, E. D.; Wassermann, E. M.; Baborie, A.; Jaros, E.; Tierney, M. C.; 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, J. B.; Schlachetzki, J. C.M.; Uphill, J.; Collinge, J.; Mead, S.; Danek, A.; Van Deerlin, V. M.; Grossman, M.; Trojanowski, J. Q.; van der Zee, J.; Van Broeckhoven, C.; Cappa, S. F.; Leber, I.; Hannequin, D.; Golfier, V.; Vercelletto, M.; Brice, A.; Nacmias, B.; Sorbi, S.; Bagnoli, S.; Piaceri, I.; Nielsen, J. E.; Hjermind, L. E.; Riemenschneider, M.; Mayhaus, M.; Ibach, B.; Gasparoni, G.; Pichler, S.; Gu, W.; Rossor, M. N.; Fox, N. C.; Warren, J. D.; Spillantini, M. G.; Morris, H. R.; Rizzu, P.; Heutink, P.; Snowden, J. S.; Rollinson, S.; Richardson, A.; Gerhard, A.; Bruni, A. C.; Maletta, R.; Frangipane, F.; Cupidi, C.; Bernardi, L.; Anfossi, M.; Gallo, M.; Conidi, M. E.; Smirne, N.; Rademakers, R.; Baker, M.; Dickson, D. W.; Graff-Radford, N. R.; Petersen, R. C.; Knopman, D.; Josephs, K. A.; Boeve, B. F.; Parisi, J. E.; Seeley, W. W.; Miller, B. L.; Karydas, A. M.; Rosen, H.; van Swieten, J. C.; Dopper, E. G.P.; Seelaar, H.; Scheltens, P.; Logroscino, G.; Capozzo, R.; Novelli, V.; Puca, A. A.; Franceschi, M.; Postiglione, A.; Milan, G.; Sorrentino, P.; Kristiansen, M.; Chiang, H. H.; Graff, C.; Pasquier, F.; Rollin, A.; Deramecourt, V.; Lebouvier, T.; Kapogiannis, D.; Ferrucci, L.; Pickering-Brown, S.; Singleton, A. B.; Hardy, J.; Momeni, P.

In: Scientific reports, Vol. 7, No. 1, 8899, 01.12.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS

AU - Taskesen, E.

AU - Mishra, A.

AU - van der Sluis, S.

AU - Ferrari, R.

AU - Veldink, J. H.

AU - van Es, M. A.

AU - Smit, A. B.

AU - Posthuma, D.

AU - Pijnenburg, Y.

AU - Hernandez, D. G.

AU - Nalls, M. A.

AU - Rohrer, J. D.

AU - Ramasamy, A.

AU - Kwok, J. B.J.

AU - Dobson-Stone, C.

AU - Schofield, P. R.

AU - Halliday, G. M.

AU - Hodges, J. R.

AU - Piguet, O.

AU - Bartley, L.

AU - Thompson, E.

AU - Haan, E.

AU - Hernández, I.

AU - Ruiz, A.

AU - Boada, M.

AU - Borroni, B.

AU - Padovani, A.

AU - Cruchaga, C.

AU - Cairns, N. J.

AU - Benussi, L.

AU - Binetti, G.

AU - Ghidoni, R.

AU - Forloni, G.

AU - Albani, D.

AU - Galimberti, D.

AU - Fenoglio, C.

AU - Serpente, M.

AU - Scarpini, E.

AU - Clarimón, J.

AU - Lleó, A.

AU - Blesa, R.

AU - Waldö, M. Landqvist

AU - Nilsson, K.

AU - Nilsson, C.

AU - Mackenzie, I. R.A.

AU - Hsiung, G. Y.R.

AU - Mann, D. M.A.

AU - Grafman, Jordan Henry

AU - Morris, C. M.

AU - Attems, J.

AU - Griffiths, T. D.

AU - McKeith, I. G.

AU - Thomas, A. J.

AU - Pietrini, P.

AU - Huey, E. D.

AU - Wassermann, E. M.

AU - Baborie, A.

AU - Jaros, E.

AU - Tierney, M. C.

AU - Pastor, P.

AU - Razquin, C.

AU - Ortega-Cubero, S.

AU - Alonso, E.

AU - Perneczky, R.

AU - Diehl-Schmid, J.

AU - Alexopoulos, P.

AU - Kurz, A.

AU - Rainero, I.

AU - Rubino, E.

AU - Pinessi, L.

AU - Rogaeva, E.

AU - St George-Hyslop, P.

AU - Rossi, G.

AU - Tagliavini, F.

AU - Giaccone, G.

AU - Rowe, J. B.

AU - Schlachetzki, J. C.M.

AU - Uphill, J.

AU - Collinge, J.

AU - Mead, S.

AU - Danek, A.

AU - Van Deerlin, V. M.

AU - Grossman, M.

AU - Trojanowski, J. Q.

AU - van der Zee, J.

AU - Van Broeckhoven, C.

AU - Cappa, S. F.

AU - Leber, I.

AU - Hannequin, D.

AU - Golfier, V.

AU - Vercelletto, M.

AU - Brice, A.

AU - Nacmias, B.

AU - Sorbi, S.

AU - Bagnoli, S.

AU - Piaceri, I.

AU - Nielsen, J. E.

AU - Hjermind, L. E.

AU - Riemenschneider, M.

AU - Mayhaus, M.

AU - Ibach, B.

AU - Gasparoni, G.

AU - Pichler, S.

AU - Gu, W.

AU - Rossor, M. N.

AU - Fox, N. C.

AU - Warren, J. D.

AU - Spillantini, M. G.

AU - Morris, H. R.

AU - Rizzu, P.

AU - Heutink, P.

AU - Snowden, J. S.

AU - Rollinson, S.

AU - Richardson, A.

AU - Gerhard, A.

AU - Bruni, A. C.

AU - Maletta, R.

AU - Frangipane, F.

AU - Cupidi, C.

AU - Bernardi, L.

AU - Anfossi, M.

AU - Gallo, M.

AU - Conidi, M. E.

AU - Smirne, N.

AU - Rademakers, R.

AU - Baker, M.

AU - Dickson, D. W.

AU - Graff-Radford, N. R.

AU - Petersen, R. C.

AU - Knopman, D.

AU - Josephs, K. A.

AU - Boeve, B. F.

AU - Parisi, J. E.

AU - Seeley, W. W.

AU - Miller, B. L.

AU - Karydas, A. M.

AU - Rosen, H.

AU - van Swieten, J. C.

AU - Dopper, E. G.P.

AU - Seelaar, H.

AU - Scheltens, P.

AU - Logroscino, G.

AU - Capozzo, R.

AU - Novelli, V.

AU - Puca, A. A.

AU - Franceschi, M.

AU - Postiglione, A.

AU - Milan, G.

AU - Sorrentino, P.

AU - Kristiansen, M.

AU - Chiang, H. H.

AU - Graff, C.

AU - Pasquier, F.

AU - Rollin, A.

AU - Deramecourt, V.

AU - Lebouvier, T.

AU - Kapogiannis, D.

AU - Ferrucci, L.

AU - Pickering-Brown, S.

AU - Singleton, A. B.

AU - Hardy, J.

AU - Momeni, P.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS; n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene (ELP2). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35, and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.

AB - Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS; n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene (ELP2). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35, and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.

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U2 - 10.1038/s41598-017-09320-z

DO - 10.1038/s41598-017-09320-z

M3 - Article

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 8899

ER -