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.

中文翻译：

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黑色素瘤种系风险位点、驱动基因和合并症之间的联系：组织特异性多组学分析的见解

全基因组关联研究 (GWAS) 将 76 个基因座与发生黑色素瘤的风险相关联。然而，了解这种关联的分子基础仍然是一个挑战，因为大多数这些基因座位于基因组的非编码区域。在这里，我们整合了来自黑色素瘤相关组织和细胞类型的表观基因组标记、三维 (3D) 基因组组织和表达数量性状基因座 (eQTL) 的数据，以获得关于黑色素瘤风险机制的新见解。这种综合方法揭示了总共 151 个目标基因，它们以线性序列靠近和远离风险位点，在黑色素瘤的病因学中具有已知和新的作用。利用蛋白质-蛋白质相互作用网络，我们鉴定了与目标基因产物直接或间接相互作用的蛋白质。相互作用的蛋白质富含已知的黑色素瘤驱动基因。将这些靶基因进一步整合到组织特异性基因调控网络中，揭示了将黑色素瘤与其合并症联系起来的基因调控模式。我们的研究为与黑色素瘤风险相关的遗传变异的生物学影响提供了新的见解。