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; 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; J. 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

doi: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

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. BartleyE. 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, J. 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

Physical Medicine and Rehabilitation

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

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 language	English (US)
Article number	8899
Journal	Scientific reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-09320-z
State	Published - Dec 1 2017

Funding

We thank the International FTD-Genomics Consortium (IFGC) for providing the data of the FTD and FTD-ALS summary statistics. The acknowledgments for and the consortia members of the IFGC are shown in the Additional file text (Appendices A and B). We furthermore thank G. Coppola and D.H. Geschwind for providing information of the DNA-methylation FTD patient cohort that is used in this study. We thank Ingrosyl for their financial support to perform this study. SvdS is funded by the Netherlands Scientific Organization (NWO/ MaGW: VIDI-452-12-014).

ASJC Scopus subject areas

General

Access to Document

10.1038/s41598-017-09320-z

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., ... 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, 7(1), Article 8899. https://doi.org/10.1038/s41598-017-09320-z

@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 J. Grafman 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",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

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, 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, 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

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, J.

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.

UR - http://www.scopus.com/inward/record.url?scp=85029377334&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029377334&partnerID=8YFLogxK

U2 - 10.1038/s41598-017-09320-z

DO - 10.1038/s41598-017-09320-z

M3 - Article

C2 - 28827549

AN - SCOPUS:85029377334

SN - 2045-2322

VL - 7

JO - Scientific reports

JF - Scientific reports

IS - 1

M1 - 8899

ER -

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

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this