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Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocyte  cis -eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene,  MX2  (Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increase  MX2  levels, consistent with the  cis -eQTL of  MX2  in primary human melanocytes. Melanocyte-specific expression of human  MX2  in a zebrafish model demonstrates accelerated melanoma formation in a  BRAF  V600E  background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of  MX2  in melanoma susceptibility.

Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma