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.
Highlights
Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes
FTD co-occurs with Amyotrophic Lateral Sclerosis (FTD-Amyotrophic Lateral Sclerosis cases (ALS)), approximately seen in 15% of all FTD cases[3], which forms a reason why FTD and ALS may be considered as a disease continuum
We detected Serine Threonine Kinase 39 (STK39), which is involved in Parkinson Disease[21,22], Retinoic Acid Induced 1 (RAI1), which is involved in the control of early neural differentiation), and Solute Carrier Family 39 (SLC39A6), which belongs to a subfamily of proteins that show structural characteristics of zinc transporters[23] and which is associated with length of survival in esophageal squamous-cell carcinoma[24], and overexpressed in Frontal cortex
Summary
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. Genome-wide association studies (GWAS) have become a standard approach to identify common genetic risk variants for complex diseases. Whole genome epigenetic involvement in FTD, to identify potential associations with pathogenesis, such as degeneration of the frontal and temporal lobes, has as yet to be elucidated[13]. The exact role of genome-wide DNA-methylation for patients with FTD with or without concomitant Amyotrophic Lateral Sclerosis (FTD-ALS) has not been established. We study genome-wide DNA-methylation profiles of the FTD cases in the previous cohort (total n = 128, of which 7 cases are FTD-ALS), and separately for the clinical subtype FTD-ALS. We aimed to: (1) Explore separation of FTD clinical subtypes using the DNA-methylation profiles. (2) detect genetic variants and/or epigenetic changes that show associations with FTD and/or FTD-ALS, and (3) examine whether genetic and epigenetic risk factors for FTD and/or FTD-ALS converge into specific biological processes as these may indicate evidence for a role of epigenetics in neurodegeneration in FTD
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