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000281103 1001_ $$aKüçükali, Fahri$$b0
000281103 245__ $$aMultiomic analyses direct hypotheses for Creutzfeldt-Jakob disease risk genes.
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000281103 520__ $$aPrions 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.
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000281103 650_7 $$2Other$$amultiomics
000281103 650_7 $$2Other$$aneurodegeneration
000281103 650_7 $$2Other$$aproteome-wide association studies (PWAS)
000281103 650_7 $$2Other$$asporadic Creutzfeldt-Jakob disease (sCJD)
000281103 650_7 $$2Other$$atranscriptome-wide association studies (TWAS)
000281103 650_2 $$2MeSH$$aCreutzfeldt-Jakob Syndrome: genetics
000281103 650_2 $$2MeSH$$aCreutzfeldt-Jakob Syndrome: metabolism
000281103 650_2 $$2MeSH$$aHumans
000281103 650_2 $$2MeSH$$aGenome-Wide Association Study
000281103 650_2 $$2MeSH$$aGenetic Predisposition to Disease: genetics
000281103 650_2 $$2MeSH$$aTranscriptome: genetics
000281103 650_2 $$2MeSH$$aBrain: metabolism
000281103 650_2 $$2MeSH$$aRisk Factors
000281103 7001_ $$aHill, Elizabeth$$b1
000281103 7001_ $$aWatzeels, Tijs$$b2
000281103 7001_ $$aHummerich, Holger$$b3
000281103 7001_ $$aCampbell, Tracy$$b4
000281103 7001_ $$aDarwent, Lee$$b5
000281103 7001_ $$aCollins, Steven$$b6
000281103 7001_ $$aStehmann, Christiane$$b7
000281103 7001_ $$00000-0003-3841-5511$$aKovacs, Gabor G$$b8
000281103 7001_ $$aGeschwind, Michael D$$b9
000281103 7001_ $$aFrontzek, Karl$$b10
000281103 7001_ $$aBudka, Herbert$$b11
000281103 7001_ $$aGelpi, Ellen$$b12
000281103 7001_ $$aAguzzi, Adriano$$b13
000281103 7001_ $$avan der Lee, Sven J$$b14
000281103 7001_ $$00000-0002-2374-9204$$avan Duijn, Cornelia M$$b15
000281103 7001_ $$aLiberski, Pawel P$$b16
000281103 7001_ $$aCalero, Miguel$$b17
000281103 7001_ $$00000-0002-6081-8037$$aSanchez-Juan, Pascual$$b18
000281103 7001_ $$aBouaziz-Amar, Elodie$$b19
000281103 7001_ $$aLaplanche, Jean-Louis$$b20
000281103 7001_ $$aHaïk, Stéphane$$b21
000281103 7001_ $$aBrandel, Jean-Phillipe$$b22
000281103 7001_ $$aMammana, Angela$$b23
000281103 7001_ $$00000-0003-1631-1439$$aCapellari, Sabina$$b24
000281103 7001_ $$aPoleggi, Anna$$b25
000281103 7001_ $$aLadogana, Anna$$b26
000281103 7001_ $$aTiple, Dorina$$b27
000281103 7001_ $$0P:(DE-2719)9000358$$aZafar, Saima$$b28$$udzne
000281103 7001_ $$aBooth, Stephanie$$b29
000281103 7001_ $$aJansen, Gerard H$$b30
000281103 7001_ $$aAreškevičiūtė, Aušrinė$$b31
000281103 7001_ $$aLund, Eva Løbner$$b32
000281103 7001_ $$aGlisic, Katie$$b33
000281103 7001_ $$00000-0002-9444-9524$$aParchi, Piero$$b34
000281103 7001_ $$0P:(DE-2719)2812183$$aHermann, Peter$$b35
000281103 7001_ $$0P:(DE-2719)2000058$$aZerr, Inga$$b36$$udzne
000281103 7001_ $$aSafar, Jiri$$b37
000281103 7001_ $$aGambetti, Pierluigi$$b38
000281103 7001_ $$aAppleby, Brian S$$b39
000281103 7001_ $$aCollinge, John$$b40
000281103 7001_ $$aSleegers, Kristel$$b41
000281103 7001_ $$aMead, Simon$$b42
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