eprintid: 10047119 rev_number: 36 eprint_status: archive userid: 608 dir: disk0/10/04/71/19 datestamp: 2018-04-19 14:45:17 lastmod: 2021-09-20 00:11:39 status_changed: 2018-04-19 14:45:17 type: article metadata_visibility: show creators_name: Taskesen, E creators_name: Mishra, A creators_name: Van Der Sluis, S creators_name: Ferrari, R creators_name: Veldink, JH creators_name: Van Es, MA creators_name: Smit, AB creators_name: Posthuma, D creators_name: Pijnenburg, Y title: Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: DF9 divisions: FA5 divisions: D07 divisions: F84 divisions: F86 note: Copyright © The Author(s) 2017. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. 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. date: 2017-12-01 date_type: published official_url: http://dx.doi.org/10.1038/s41598-017-09320-z oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Journal Article verified: verified_manual elements_id: 1549470 doi: 10.1038/s41598-017-09320-z lyricists_name: Collinge, John lyricists_name: Ferrari, Raffaele lyricists_name: Fox, Nicholas lyricists_name: Hardy, John lyricists_name: Mead, Simon lyricists_name: Morris, Huw lyricists_name: Rossor, Martin lyricists_name: Smalley, June lyricists_name: Warren, Jason lyricists_id: JCOLL20 lyricists_id: RFERR12 lyricists_id: NCIFO25 lyricists_id: JHARD28 lyricists_id: SMEAD68 lyricists_id: HRMOR79 lyricists_id: MNROS52 lyricists_id: JASMA87 lyricists_id: JDWAR75 actors_name: Bracey, Alan actors_id: ABBRA90 actors_role: owner full_text_status: public publication: Scientific Reports volume: 7 article_number: 8899 issn: 2045-2322 citation: Taskesen, E; Mishra, A; Van Der Sluis, S; Ferrari, R; Veldink, JH; Van Es, MA; Smit, AB; ... Pijnenburg, Y; + view all <#> Taskesen, E; Mishra, A; Van Der Sluis, S; Ferrari, R; Veldink, JH; Van Es, MA; Smit, AB; Posthuma, D; Pijnenburg, Y; - view fewer <#> (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 , Article 8899. 10.1038/s41598-017-09320-z <https://doi.org/10.1038/s41598-017-09320-z>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10047119/1/s41598-017-09320-z.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/10047119/8/Taskesen_Susceptible_genes_disease_mechanisms_Suppl.pdf