Research On Genetic Mechanism Of Alzheimer’S Disease Susceptibility Gene PTK2B Expression Regulation

Alzheimer’s disease(AD)is the most common neurodegenerative disease,but the underlying pathogenesis of AD remains unclear.Genome-wide Association Study(GWAS)has identified a significant AD susceptibility locus in the upstream region of the PTK2 B gene.However,the investigation of the role of this locus in the pathogenesis of AD is still unknown.According to GWAS results,the single nucleotide polymorphism(SNP)rs28834970 is the strongest AD-associated variant in this locus.Based on the rs28834970 variant,the study analyzed the genetic expression regulation mechanism of PTK2 B gene and its influences on the risk of AD by bioinformatics method.Though the linkage disequilibrium analysis and genetic association analysis,the study obtained 6 SNPs in the linkage disequilibrium region identified by rs28834970,and all of the SNPs are significantly associated with AD risk that the P-values are less than 1.00E-11.The enrichment analysis based on 127 cell lines or tissues indicated that the rs28834970 locus was activated only in the enhancers elements of blood immune cell line and exerted a potential epigenetic regulation function.The study collected 3 brain tissues and 8 blood tissues eQTL data to identify the association between rs28834970 variant and PTK2 B expression by eQTL analysis.The results showed that rs28834970 allele “C” significantly positively regulates the expression of PTK2 B in peripheral blood tissue.The regression coefficients "β" of the eight blood tissues eQTL analysis results were greater than 0.1 or the Z-values were greater than 15,the P-values were less than 0.01,and the lowest one was 5.98E-165.However,the P-values of the brain tissue eQTL results were all greater than 0.1.Through meta-analysis,the study integrated the results of eight blood tissues eQTL datasets as a tool variable for blood tissue PTK2 B gene expression to conduct Mendelian randomization(MR)studies.MR analysis revealed that high expression of PTK2 B gene in blood tissue significantly increases the AD risk.(β=0.373,P=3.22E-09).In summary,the study found that AD susceptibility locus rs28834970 has a positive expression regulation on PTK2 B gene only in blood tissue,and the high expression of PTK2 B gene in blood tissue increases the AD risk.Besides,the study constructed a complete GWAS follow-up bioinformatics analysis pipeline,and firstly proposed PTK2 B gene and its encoded protein Pyk2 in blood tissue as a potential biomarker for the diagnosis and treatment of AD.