ZFIN ID: ZDB-PUB-200603-14
Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma
Choi, J., Zhang, T., Vu, A., Ablain, J., Makowski, M.M., Colli, L.M., Xu, M., Hennessey, R.C., Yin, J., Rothschild, H., Gräwe, C., Kovacs, M.A., Funderburk, K.M., Brossard, M., Taylor, J., Pasaniuc, B., Chari, R., Chanock, S.J., Hoggart, C.J., Demenais, F., Barrett, J.H., Law, M.H., Iles, M.M., Yu, K., Vermeulen, M., Zon, L.I., Brown, K.M.
Date: 2020
Source: Nature communications   11: 2718 (Journal)
Registered Authors: Taylor, John, Zon, Leonard I.
Keywords: none
MeSH Terms:
  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Gene Expression Regulation
  • Genes, Reporter/genetics
  • Genetic Predisposition to Disease/genetics*
  • Genome-Wide Association Study/methods*
  • HEK293 Cells
  • Humans
  • Melanocytes/metabolism
  • Melanoma/genetics*
  • Melanoma/pathology
  • Mutation*
  • Myxovirus Resistance Proteins/genetics*
  • Polymorphism, Single Nucleotide*
  • Proto-Oncogene Proteins B-raf/genetics
  • Proto-Oncogene Proteins B-raf/metabolism
  • Quantitative Trait Loci/genetics
  • Zebrafish/genetics
  • Zebrafish/metabolism
PubMed: 32483191 Full text @ Nat. Commun.
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 BRAFV600E background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility.