Identification of Novel Proteins for Creutzfeldt-Jakob Disease by Integrating Genome-wide Association Data and Human Brain Proteomes
10.13865/j.cnki.cjbmb.2025.06.1087
- VernacularTitle:通过全基因组关联数据和人脑蛋白质组的综合分析鉴定与克雅氏病相关蛋白质
- Author:
Wan-Ting ZHONG
1
;
Yi-Tong YUAN
;
Min ZHANG
;
Ruo-Chen DU
;
Ling-Yu ZHANG
;
Chun-Fang WANG
Author Information
1. 山西医科大学医学科学院药学系
- Publication Type:Journal Article
- Keywords:
Creutzfeldt-Jakob disease(CJD);
Mendelian randomization;
quantitative trait locus(QTL);
syntaxin 6(STX6);
protein disulfide isomerase family A member 4(PDIA4)
- From:
Chinese Journal of Biochemistry and Molecular Biology
2025;41(7):1040-1047,中插1-中插26
- CountryChina
- Language:Chinese
-
Abstract:
Creutzfeldt-Jakob disease(CJD)is a rare neurodegenerative disorder characterized by abnor-malities in the prion protein(PrP),the most common form of human prion disease.Although Genome-Wide Association Studies(GWAS)have identified numerous risk genes for CJD,the mechanisms under-lying these risk loci remain poorly understood.This study aims to elucidate novel genetically prioritized candidate proteins associated with CJD in the human brain through an integrative analytical pipeline.Uti-lizing datasets from Protein Quantitative Trait Loci(pQTL)(NpQTL1=152,NpQTL2=376),expres-sion QTL(eQTL)(N=452),and the CJD GWAS(NCJD=4 110,NControls=13 569),we imple-mented a systematic analytical pipeline.This pipeline included Proteome-Wide Association Study(PWAS),Mendelian randomization(MR),Bayesian colocalization,and Transcriptome-Wide Associa-tion Study(TWAS)to identify novel genetically prioritized candidate proteins implicated in CJD patho-genesis within the brain.Through PWAS,we identified that the altered abundance of six brain proteins was significantly associated with CJD.Two genes,STX6 and PDIA4,were established as lead causal genes for CJD,supported by robust evidence(False Discovery Rate＜0.05 in MR analysis;PP4/(PP3+PP4)≥0.75 in Bayesian colocalization).Specifically,elevated levels of STX6 and PDIA4 were asso-ciated with an increased risk of CJD.Additionally,TWAS demonstrated that STX6 and PDIA4 were asso-ciated with CJD at the transcriptional level.
