Multiomic analyses direct hypotheses for Creutzfeldt-Jakob disease risk genes

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal transmissible neurodegenerative disorder.
• The molecular risk factors for sCJD beyond prion protein variations are not well understood.
• Understanding sCJD mechanisms may offer insights into other common neurodegenerative disorders.

Purpose of the Study:

• To identify and prioritize genes conferring risk for sCJD.
• To elucidate molecular mechanisms underlying sCJD susceptibility.
• To explore novel risk factors and pathways beyond known sCJD loci.

Main Methods:

• Integrated genome-wide association study (GWAS) data with brain gene and protein expression datasets.
• Performed transcriptome-wide and proteome-wide association studies (TWAS & PWAS).
• Utilized Bayesian genetic colocalization and a systematic gene prioritization pipeline.

Main Results:

• Upregulation of syntaxin-6 (STX6) gene and protein expression in the brain, particularly in oligodendrocytes, associated with sCJD risk.
• Increased gene and protein expression of protein disulfide isomerase family A member 4 (PDIA4), linked to unfolded protein response in excitatory neurons, associated with sCJD risk.
• Mesencephalic astrocyte derived neurotrophic factor (MANF) protein expression showed a protective effect against sCJD.

Conclusions:

• Identified 32 prioritized sCJD risk genes and associated molecular mechanisms.
• Highlighted the role of glial cells, sulfatides, and excitatory neuron unfolded protein response in sCJD pathogenesis.
• Provided novel hypotheses for sCJD research beyond the prion protein and established risk loci.