Multiomics Study Of Risk Genes And Pathogenesis For Parkinson's Disease

The genome-wide association study(GWAS)has identified several genetic variants associated with Parkinson's disease(PD).However,the genes or functional DNA elements that affect traits through these genetic variations are often unknown.In this study,by integrating GWAS,expression quantitative trait locus(e QTL)and methylation quantitative trait loci,the risk genes of PD were identified and their potential pathogenesis was analyzed.First,the meta-analysis was used to integrate the GWAS data of the two groups,and obtained a total of over 6 million single nucleotide polymorphism sites,of which 1,678 were significantly correlated with PD(BHadjusted p-value < 7.83e-09).Enrichment analysis of these significant sites involves PD-related pathways,which indicates that the meta-analyzed GWAS data can reflect the pathological features of PD.Next,using summary data-based Mendelian randomization and heterogeneity testing methods,combined with meta-analysis GWAS data and e QTL data to identify PD risk genes.There are four genes that have been significant in the meta-analysis of GWAS results: CRHR1,KANSL1,NSF and LRRC37A;And two new risk genes STX4 and BST1 are found.The most significant CRHR1 is the target of the approved drug hydrocortisone,so hydrocortisone may be a potential drug for the treatment of PD.Finally,this study combined with multi-omics data to analyze the underlying pathogenic mechanism of PD risk genes.By screening and annotating 51,940 DNA methylation sites related to the expression probe,the role of DNA methylation in transcription is clarified,and the potential pathogenic mechanism of two genes is further explored:(1)When the DNA methylation level of CRHR1 promoter is low,the repressor binds to the promoter,thereby inhibiting the transcription of CRHR1 and increasing the risk of PD;(2)When the DNA methylation level of the promoter region of LRRC37A4 is low,the transcription factor and promoter are combined,thereby promoting the expression of LRRC37A4 and increasing the risk of PD.This research identified the risk genes and potential pathogenesis that affect PD,which has significance for the diagnosis and treatment of PD.