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Genome‐wide association studies (GWAS) have associated 76 loci with the risk of developing melanoma. However, understanding the molecular basis of such associations has remained a challenge because most of these loci are in non‐coding regions of the genome. Here, we integrated data on epigenomic markers, three‐dimensional (3D) genome organization, and expression quantitative trait loci (eQTL) from melanoma‐relevant tissues and cell types to gain novel insights into the mechanisms underlying melanoma risk. This integrative approach revealed a total of 151 target genes, both near and far away from the risk loci in linear sequence, with known and novel roles in the etiology of melanoma. Using protein–protein interaction networks, we identified proteins that interact—directly or indirectly—with the products of the target genes. The interacting proteins were enriched for known melanoma driver genes. Further integration of these target genes into tissue‐specific gene regulatory networks revealed patterns of gene regulation that connect melanoma to its comorbidities. Our study provides novel insights into the biological implications of genetic variants associated with melanoma risk.

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 5254 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 in HEK293 cells. The identified regulatory variant(s) typically did not match the original tag variant within the PD associated locus, supporting the need for deeper exploration of these loci. The existence of allele specific transcriptional impacts within HEK293 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.