Background

Both epidemiological and clinical studies have suggested the comorbidity between cutaneous melanoma (CM) and obesity-related physical traits. However, it remains unclear about their shared genetic architecture.

Objective

To determine the shared genetic architecture between CM and obesity-related physical traits through conditional false discovery rate (cFDR) analysis.

Method

Quantile–quantile plots were firstly built to assess the pleiotropic enrichment of shared single nucleotide polymorphisms between CM and each trait. Then, cFDR and conjunctional cFDR (ccFDR) were used to identify the shared risk loci between CM and each trait. Moreover, the functional evaluation of shared risk genes was carried out through analyses of expression quantitative trait loci (eQTL), Kyoto Encyclopedia of Genes and Genomes and gene ontology, respectively. Finally, single-cell sequence analysis was performed to locate the expression of eQTL-mapped genes in tissues.

Results

Successive pleiotropic enrichment was found between CM and 5 obesity-related traits or height. 24 shared risk loci were identified between CM and 13 traits except appendicular lean mass using ccFDR analysis, with 17 novel and 4 validated loci. The functions of ccFDR-identified and eQTL-mapped genes were revealed to be mainly involved in cellular senescence, proliferation, meiotic nuclear division, cell cycle, and the metabolism of lipid, cholesterol and glucose. Single-cell sequence analysis showed that keratinocytes contribute to the occurrence and aggressiveness of CM through secreting paracrine cytokines.

Conclusion

Our findings demonstrate the significant genetic correlation between CM and obesity-related physical traits, which may provide a novel genetical basis for the pathogenesis and treatment of CM.

中文翻译：

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通过 cFDR 鉴定皮肤黑色素瘤与肥胖相关身体特征之间的全基因组遗传联系

背景

流行病学和临床研究都表明皮肤黑色素瘤（CM）和肥胖相关身体特征之间存在共病。然而，目前尚不清楚它们共有的遗传结构。

客观的

通过条件错误发现率 (cFDR) 分析确定 CM 和肥胖相关身体特征之间的共享遗传结构。

方法

首先建立分位数-分位数图来评估 CM 和每个性状之间共享的单核苷酸多态性的多效性富集。然后，使用 cFDR 和联合 cFDR (ccFDR) 来识别 CM 和每个性状之间的共享风险位点。此外，分别通过表达数量性状位点（eQTL）、京都基因与基因组百科全书和基因本体分析进行了共享风险基因的功能评估。最后，进行单细胞序列分析以定位组织中 eQTL 映射基因的表达。

结果

在 CM 和 5 种肥胖相关性状或身高之间发现了连续的多效性富集。使用 ccFDR 分析，在 CM 和除阑尾瘦体重之外的 13 个性状之间确定了 24 个共有风险位点，其中 17 个新位点和 4 个经过验证的位点。ccFDR鉴定和eQTL定位基因的功能主要涉及细胞衰老、增殖、减数分裂核分裂、细胞周期以及脂质、胆固醇和葡萄糖的代谢。单细胞序列分析表明，角质形成细胞通过分泌旁分泌细胞因子促进CM的发生和侵袭性。

结论

我们的研究结果证明了 CM 和肥胖相关身体特征之间存在显着的遗传相关性，这可能为 CM 的发病机制和治疗提供新的遗传基础。