Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma
Jiyeon Choi, Tongwu Zhang, Andrew Vu, Julien Ablain, Matthew Makowski, Leandro M. Colli, Mai Xu, Rebecca C. Hennessey, Jinhu Yin, Harriet Rothschild, Cathrin Gräwe, Michael A. Kovacs, Karen Funderburk, Myriam Brossard, John Taylor, Bogdan Paşaniuc, Raj Chari, Stephen J. Chanock, Clive Hoggart, Florence Démenais, Jennifer H. Barrett, Matthew H. Law, Mark M. Iles, Kai Yu, Michiel Vermeulen, Leonard I. Zon, Kevin M. Brown
Abstract
Abstract 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.