Genome-wide association study (GWAS) has seen great strides in revealing initial insights into the genetic architecture of Parkinson’s disease (PD). Since GWAS signals often reside in non-coding regions, relatively few of the associations have implicated specific biological mechanisms. Here, we aimed to integrate the GWAS results with large-scale expression quantitative trait loci (eQTL) in 13 brain tissues to identify candidate causal genes for PD. We conducted a transcriptome-wide association study (TWAS) for PD using the summary statistics of over 480,000 individuals from the most recent PD GWAS. We identified 18 genes significantly associated with PD after Bonferroni corrections. The most significant gene, LRRC37A2, was associated with PD in all 13 brain tissues, such as in the hypothalamus (P = 6.12 × 10−22) and nucleus accumbens basal ganglia (P = 5.62 × 10−21). We also identified eight conditionally independent genes, including four new genes at known PD loci: CD38, LRRC37A2, RNF40, and ZSWIM7. Through conditional analyses, we demonstrated that several of the GWAS significant signals on PD could be driven by genetically regulated gene expression. The most significant TWAS gene LRRC37A2 accounts for 0.855 of the GWAS signal at its loci, and ZSWIM7 accounts for all the GWAS signals at its loci. We further identified several phenotypes previously associated with PD by querying the single nucleotide polymorphisms (SNPs) in the final model of the identified genes in phenome databases. In conclusion, we prioritized genes that are likely to affect PD by using a TWAS approach and identified phenotypes associated with PD.
microRNAs (miRs) serve primary roles in certain human malignancies; however, the detailed regulatory mechanism of miR-200a in glioma progression is yet to be fully elucidated. The current study aimed to assess the expression of miR-200a in glioma as well as the regulatory mechanism of miR-200a in glioma cell proliferation, survival and invasion. RT-qPCR and western blotting were performed to examine mRNA and protein expression. An MTT assay, an EdU incorporation cell proliferation assay and a transwell assay were utilized to assess cell survival, proliferation and invasion. The results indicated that the miR-200a levels were significantly reduced in glioma tissues compared with normal brain tissues. Levels were also downregulated in glioma cell lines when compared with those in normal human astrocyte cells. Furthermore, low miR-200a expression was associated with advanced progression of glioma. The overexpression of miR-200a inhibited glioma cell proliferation, survival and invasion. Results also identified that FOXA1 was a target gene of miR-200a in glioma cells and that the increased expression of FOXA1 was negatively correlated to the decreased expression of miR-200a in glioma tissues. Furthermore, FOXA1 expression was negatively mediated by miR-200a in glioma cells and the overexpression of FOXA1 eliminated the inhibitory effects of miR-200a on the survival, proliferation and invasion of glioma cells. In conclusion, the current study demonstrated that miR-200a functions acts as a tumor suppressor in glioma by directly targeting FOXA1 and may thus be a potential candidate for the treatment of glioma.
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