TY  - JOUR
AU  - Küçükali, Fahri
AU  - Hill, Elizabeth
AU  - Watzeels, Tijs
AU  - Hummerich, Holger
AU  - Campbell, Tracy
AU  - Darwent, Lee
AU  - Collins, Steven
AU  - Stehmann, Christiane
AU  - Kovacs, Gabor G
AU  - Geschwind, Michael D
AU  - Frontzek, Karl
AU  - Budka, Herbert
AU  - Gelpi, Ellen
AU  - Aguzzi, Adriano
AU  - van der Lee, Sven J
AU  - van Duijn, Cornelia M
AU  - Liberski, Pawel P
AU  - Calero, Miguel
AU  - Sanchez-Juan, Pascual
AU  - Bouaziz-Amar, Elodie
AU  - Laplanche, Jean-Louis
AU  - Haïk, Stéphane
AU  - Brandel, Jean-Phillipe
AU  - Mammana, Angela
AU  - Capellari, Sabina
AU  - Poleggi, Anna
AU  - Ladogana, Anna
AU  - Tiple, Dorina
AU  - Zafar, Saima
AU  - Booth, Stephanie
AU  - Jansen, Gerard H
AU  - Areškevičiūtė, Aušrinė
AU  - Lund, Eva Løbner
AU  - Glisic, Katie
AU  - Parchi, Piero
AU  - Hermann, Peter
AU  - Zerr, Inga
AU  - Safar, Jiri
AU  - Gambetti, Pierluigi
AU  - Appleby, Brian S
AU  - Collinge, John
AU  - Sleegers, Kristel
AU  - Mead, Simon
TI  - Multiomic analyses direct hypotheses for Creutzfeldt-Jakob disease risk genes.
JO  - Brain
VL  - 148
IS  - 9
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2025-01064
SP  - 3350 - 3363
PY  - 2025
AB  - 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.
KW  - Creutzfeldt-Jakob Syndrome: genetics
KW  - Creutzfeldt-Jakob Syndrome: metabolism
KW  - Humans
KW  - Genome-Wide Association Study
KW  - Genetic Predisposition to Disease: genetics
KW  - Transcriptome: genetics
KW  - Brain: metabolism
KW  - Risk Factors
KW  - multiomics (Other)
KW  - neurodegeneration (Other)
KW  - proteome-wide association studies (PWAS) (Other)
KW  - sporadic Creutzfeldt-Jakob disease (sCJD) (Other)
KW  - transcriptome-wide association studies (TWAS) (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:39865733
C2  - pmc:PMC12404779
DO  - DOI:10.1093/brain/awaf032
UR  - https://pub.dzne.de/record/281103
ER  -