Department of Dermato-Venereology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Genes Genomics. 2023 Dec;45(12):1549-1562. doi: 10.1007/s13258-023-01446-x. Epub 2023 Sep 28.
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.
To determine the shared genetic architecture between CM and obesity-related physical traits through conditional false discovery rate (cFDR) analysis.
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.
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.
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.
流行病学和临床研究均表明皮肤黑色素瘤（CM）与肥胖相关的身体特征存在共病现象。然而，它们之间的共享遗传结构仍不清楚。
通过条件假发现率（cFDR）分析确定 CM 与肥胖相关身体特征之间的共享遗传结构。
首先构建分位数-分位数图，以评估 CM 与每种特征之间共享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 与每种特征之间的共享风险基因座。此外，通过分析表达数量性状基因座（eQTL）、京都基因与基因组百科全书和基因本体论，分别对共享风险基因进行功能评估。最后，进行单细胞序列分析以定位 eQTL 映射基因在组织中的表达。
CM 与 5 种肥胖相关特征或身高之间存在连续的多效性富集。使用 ccFDR 分析在 CM 与除四肢瘦组织质量外的 13 种特征之间确定了 24 个共享风险基因座，其中包括 17 个新的和 4 个已验证的基因座。ccFDR 鉴定和 eQTL 映射基因的功能揭示其主要涉及细胞衰老、增殖、减数核分裂、细胞周期以及脂质、胆固醇和葡萄糖代谢。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参与 CM 的发生和侵袭。
我们的研究结果表明 CM 与肥胖相关身体特征之间存在显著的遗传相关性，这可能为 CM 的发病机制和治疗提供新的遗传基础。
