Hulur Imge, Skol Andrew D, Gamazon Eric R, Cox Nancy J, Onel Kenan
Committee on Genetics, Genomics and Systems Biology, The University of Chicago, Chicago, Illinois, United States of America.
Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
PLoS One. 2017 Oct 3;12(10):e0185730. doi: 10.1371/journal.pone.0185730. eCollection 2017.
Melanoma is the deadliest form of skin cancer and presents a significant health care burden in many countries. In addition to ultraviolet radiation in sunlight, the main causal factor for melanoma, genetic factors also play an important role in melanoma susceptibility. Although genome-wide association studies have identified many single nucleotide polymorphisms associated with melanoma, little is known about the proportion of disease risk attributable to these loci and their distribution throughout the genome. Here, we investigated the genetic architecture of melanoma in 1,888 cases and 990 controls of European non-Hispanic ancestry. We estimated the overall narrow-sense heritability of melanoma to be 0.18 (P < 0.03), indicating that genetics contributes significantly to the risk of sporadically-occurring melanoma. We then demonstrated that only a small proportion of this risk is attributable to known risk variants, suggesting that much remains unknown of the role of genetics in melanoma. To investigate further the genetic architecture of melanoma, we partitioned the heritability by chromosome, minor allele frequency, and functional annotations. We showed that common genetic variation contributes significantly to melanoma risk, with a risk model defined by a handful of genomic regions rather than many risk loci distributed throughout the genome. We also demonstrated that variants affecting gene expression in skin account for a significant proportion of the heritability, and are enriched among melanoma risk loci. Finally, by incorporating skin color into our analyses, we observed both a shift in significance for melanoma-associated loci and an enrichment of expression quantitative trait loci among melanoma susceptibility variants. These findings suggest that skin color may be an important modifier of melanoma risk. We speculate that incorporating skin color and other non-genetic factors into genetic studies may allow for an improved understanding of melanoma susceptibility and guide future investigations to identify melanoma risk genes.
黑色素瘤是最致命的皮肤癌形式，在许多国家都带来了重大的医疗负担。除了阳光中的紫外线辐射（黑色素瘤的主要致病因素）外，遗传因素在黑色素瘤易感性中也起着重要作用。尽管全基因组关联研究已经确定了许多与黑色素瘤相关的单核苷酸多态性，但对于这些基因座所导致的疾病风险比例及其在整个基因组中的分布知之甚少。在此，我们对1888例欧洲非西班牙裔血统的病例和990例对照进行了黑色素瘤的遗传结构研究。我们估计黑色素瘤的总体狭义遗传率为0.18（P < 0.03），这表明遗传学对散发性黑色素瘤的风险有显著贡献。然后我们证明，这种风险中只有一小部分可归因于已知的风险变异，这表明遗传学在黑色素瘤中的作用仍有许多未知之处。为了进一步研究黑色素瘤的遗传结构，我们按染色体、次要等位基因频率和功能注释对遗传率进行了划分。我们表明，常见的遗传变异对黑色素瘤风险有显著贡献，其风险模型由少数几个基因组区域定义，而非分布在整个基因组中的许多风险基因座。我们还证明，影响皮肤中基因表达的变异占遗传率的很大一部分，并且在黑色素瘤风险基因座中富集。最后，通过将肤色纳入我们的分析，我们观察到与黑色素瘤相关的基因座的显著性发生了变化，并且在黑色素瘤易感性变异中表达数量性状基因座富集。这些发现表明肤色可能是黑色素瘤风险的一个重要调节因素。我们推测，将肤色和其他非遗传因素纳入遗传研究可能有助于更好地理解黑色素瘤易感性，并指导未来识别黑色素瘤风险基因的研究。
