Identification of genomic-wide genetic links between cutaneous melanoma and obesity-related physical traits via cFDR

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.