İnce haritalama, Parkinson hastalığı ile ilgili lokusta 27 alel spesifik MPRA düzenleyici varyantı tanımlar

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Abstract Genome wide association studies (GWAS) have identified a number of genomic loci that are associated with Parkinson’s disease (PD) risk. However, the majority of these variants lie in non-coding regions, and thus the mechanisms by which they influence disease development, and/or potential subtypes, remain largely elusive. To address this, we used a massively parallel reporter assay (MPRA) to screen the regulatory function of 5,254 variants that have a known or putative connection to PD. We identified 138 loci with enhancer activity, of which 27 exhibited allele-specific regulatory activity. The identified regulatory variant(s) typically did not match the original PD GWAS tag variant within the PD associated locus, supporting the need for deeper exploration of these loci. The existence of allele specific transcriptional impacts within cells, confirms that at least a subset of the PD associated regions mark functional gene regulatory elements. Future functional studies that confirm the putative targets of the empirically verified regulatory variants will be crucial for gaining a greater understanding of how gene regulatory network(s) modulate PD risk.

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