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@ARTICLE{Kkali:281103,
      author       = {Küçükali, Fahri and Hill, Elizabeth and Watzeels, Tijs
                      and Hummerich, Holger and Campbell, Tracy and Darwent, Lee
                      and Collins, Steven and Stehmann, Christiane and Kovacs,
                      Gabor G and Geschwind, Michael D and Frontzek, Karl and
                      Budka, Herbert and Gelpi, Ellen and Aguzzi, Adriano and van
                      der Lee, Sven J and van Duijn, Cornelia M and Liberski,
                      Pawel P and Calero, Miguel and Sanchez-Juan, Pascual and
                      Bouaziz-Amar, Elodie and Laplanche, Jean-Louis and Haïk,
                      Stéphane and Brandel, Jean-Phillipe and Mammana, Angela and
                      Capellari, Sabina and Poleggi, Anna and Ladogana, Anna and
                      Tiple, Dorina and Zafar, Saima and Booth, Stephanie and
                      Jansen, Gerard H and Areškevičiūtė, Aušrinė and Lund,
                      Eva Løbner and Glisic, Katie and Parchi, Piero and Hermann,
                      Peter and Zerr, Inga and Safar, Jiri and Gambetti, Pierluigi
                      and Appleby, Brian S and Collinge, John and Sleegers,
                      Kristel and Mead, Simon},
      title        = {{M}ultiomic analyses direct hypotheses for
                      {C}reutzfeldt-{J}akob disease risk genes.},
      journal      = {Brain},
      volume       = {148},
      number       = {9},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2025-01064},
      pages        = {3350 - 3363},
      year         = {2025},
      abstract     = {Prions are assemblies of misfolded prion protein that cause
                      several fatal and transmissible neurodegenerative diseases,
                      with the most common phenotype in humans being sporadic
                      Creutzfeldt-Jakob disease (sCJD). Aside from variation of
                      the prion protein itself, molecular risk factors are not
                      well understood. Prion and prion-like mechanisms are thought
                      to underpin common neurodegenerative disorders meaning that
                      the elucidation of mechanisms could have broad relevance.
                      Herein we sought to further develop our understanding of the
                      factors that confer risk of sCJD using a systematic gene
                      prioritization and functional interpretation pipeline based
                      on multiomic integrative analyses. We integrated the
                      published sCJD genome-wide association study summary
                      statistics with publicly available bulk brain and brain cell
                      type gene and protein expression datasets. We performed
                      multiple transcriptome and proteome-wide association studies
                      and Bayesian genetic colocalization analyses between sCJD
                      risk association signals and multiple brain molecular
                      quantitative trait loci signals. We then applied our
                      systematic gene prioritization pipeline to the obtained
                      results and nominated prioritized sCJD risk genes with
                      risk-associated molecular mechanisms in a transcriptome and
                      proteome-wide manner. Genetic upregulation of both gene and
                      protein expression of syntaxin-6 (STX6) in the brain was
                      associated with sCJD risk in multiple datasets, with a
                      risk-associated gene expression regulation specific to
                      oligodendrocytes. Similarly, increased gene and protein
                      expression of protein disulfide isomerase family A member 4
                      (PDIA4), involved in the unfolded protein response, was
                      linked to increased disease risk, particularly in excitatory
                      neurons. Protein expression of mesencephalic astrocyte
                      derived neurotrophic factor (MANF), involved in protection
                      against endoplasmic reticulum stress and sulfatide binding
                      (linking to the enzyme in the final step of sulfatide
                      synthesis, encoded by sCJD risk gene GAL3ST1), was
                      identified as protective against sCJD. In total 32 genes
                      were prioritized into two tiers based on the level of
                      evidence and confidence for further studies. This study
                      provides insights into the genetically-associated molecular
                      mechanisms underlying sCJD susceptibility and prioritizes
                      several specific hypotheses for exploration beyond the prion
                      protein itself, as well as beyond the previously highlighted
                      sCJD risk loci, through the newly prioritized sCJD risk
                      genes and mechanisms. These findings highlight the
                      importance of glial cells, sulfatides and the excitatory
                      neuron unfolded protein response in sCJD pathogenesis.},
      keywords     = {Creutzfeldt-Jakob Syndrome: genetics / Creutzfeldt-Jakob
                      Syndrome: metabolism / Humans / Genome-Wide Association
                      Study / Genetic Predisposition to Disease: genetics /
                      Transcriptome: genetics / Brain: metabolism / Risk Factors /
                      multiomics (Other) / neurodegeneration (Other) /
                      proteome-wide association studies (PWAS) (Other) / sporadic
                      Creutzfeldt-Jakob disease (sCJD) (Other) /
                      transcriptome-wide association studies (TWAS) (Other)},
      cin          = {AG Zerr},
      ddc          = {610},
      cid          = {I:(DE-2719)1440011-1},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39865733},
      pmc          = {pmc:PMC12404779},
      doi          = {10.1093/brain/awaf032},
      url          = {https://pub.dzne.de/record/281103},
}