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@ARTICLE{Fodder:258679,
      author       = {Fodder, Katherine and Murthy, Megha and Rizzu, Patrizia and
                      Toomey, Christina E and Hasan, Rahat and Humphrey, Jack and
                      Raj, Towfique and Lunnon, Katie and Mill, Jonathan and
                      Heutink, Peter and Lashley, Tammaryn and Bettencourt,
                      Conceição},
      title        = {{B}rain {DNA} methylomic analysis of frontotemporal lobar
                      degeneration reveals {OTUD}4 in shared dysregulated
                      signatures across pathological subtypes.},
      journal      = {Acta neuropathologica},
      volume       = {146},
      number       = {1},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DZNE-2023-00652},
      pages        = {77 - 95},
      year         = {2023},
      abstract     = {Frontotemporal lobar degeneration (FTLD) is an umbrella
                      term describing the neuropathology of a clinically,
                      genetically and pathologically heterogeneous group of
                      diseases, including frontotemporal dementia (FTD) and
                      progressive supranuclear palsy (PSP). Among the major FTLD
                      pathological subgroups, FTLD with TDP-43 positive inclusions
                      (FTLD-TDP) and FTLD with tau-positive inclusions (FTLD-tau)
                      are the most common, representing about $90\%$ of the cases.
                      Although alterations in DNA methylation have been
                      consistently associated with neurodegenerative diseases,
                      including Alzheimer's disease and Parkinson's disease,
                      little is known for FTLD and its heterogeneous subgroups and
                      subtypes. The main goal of this study was to investigate DNA
                      methylation variation in FTLD-TDP and FTLD-tau. We used
                      frontal cortex genome-wide DNA methylation profiles from
                      three FTLD cohorts (142 FTLD cases and 92 controls),
                      generated using the Illumina 450K or EPIC microarrays. We
                      performed epigenome-wide association studies (EWAS) for each
                      cohort followed by meta-analysis to identify shared
                      differentially methylated loci across FTLD
                      subgroups/subtypes. In addition, we used weighted gene
                      correlation network analysis to identify co-methylation
                      signatures associated with FTLD and other disease-related
                      traits. Wherever possible, we also incorporated relevant
                      gene/protein expression data. After accounting for a
                      conservative Bonferroni multiple testing correction, the
                      EWAS meta-analysis revealed two differentially methylated
                      loci in FTLD, one annotated to OTUD4 (5'UTR-shore) and the
                      other to NFATC1 (gene body-island). Of these loci, OTUD4
                      showed consistent upregulation of mRNA and protein
                      expression in FTLD. In addition, in the three independent
                      co-methylation networks, OTUD4-containing modules were
                      enriched for EWAS meta-analysis top loci and were strongly
                      associated with the FTLD status. These co-methylation
                      modules were enriched for genes implicated in the ubiquitin
                      system, RNA/stress granule formation and glutamatergic
                      synaptic signalling. Altogether, our findings identified
                      novel FTLD-associated loci, and support a role for DNA
                      methylation as a mechanism involved in the dysregulation of
                      biological processes relevant to FTLD, highlighting novel
                      potential avenues for therapeutic development.},
      keywords     = {Humans / Frontotemporal Dementia: pathology /
                      Frontotemporal Lobar Degeneration: pathology / Brain:
                      pathology / Pick Disease of the Brain: pathology / DNA / tau
                      Proteins: metabolism / Ubiquitin-Specific Proteases:
                      metabolism / Co-methylation (Other) / DNA methylation
                      (Other) / EWAS (Other) / Frontotemporal dementia (Other) /
                      Human brain tissue (Other) / Progressive supranuclear palsy
                      (Other) / DNA (NLM Chemicals) / tau Proteins (NLM Chemicals)
                      / OTUD4 protein, human (NLM Chemicals) / Ubiquitin-Specific
                      Proteases (NLM Chemicals)},
      cin          = {AG Rizzu / AG Heutink 1},
      ddc          = {610},
      cid          = {I:(DE-2719)1210009 / I:(DE-2719)1210002},
      pnm          = {354 - Disease Prevention and Healthy Aging (POF4-354)},
      pid          = {G:(DE-HGF)POF4-354},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37149835},
      pmc          = {pmc:PMC10261190},
      doi          = {10.1007/s00401-023-02583-z},
      url          = {https://pub.dzne.de/record/258679},
}