Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Abstract

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 melanoma cases (67% newly-genotyped) and 375,188 controls identified 54 significant loci with 68 independent SNPs. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with nevus count and hair color GWAS, and transcriptome association approaches, uncovered 31 potential secondary loci, for a total of 85 cutaneous melanoma susceptibility loci. These findings provide substantial insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation, and telomere maintenance together with identifying potential new pathways for cutaneous melanoma pathogenesis.

Inflammatory Bowel Disease Risk Variants Are Associated with an Increased Risk of Skin Cancer

“…In a recent meta-analysis with 30,134 cases of melanoma and 375,188 controls, association between melanoma and IL2RA was not described. 42 Given the established role of IL-2 in the treatment of melanoma, the finding in this study warrants further investigation. In IBD, rs61839660 (T) is associated with an increased risk of Crohn’s disease (OR 1.28; posterior probability 0.999) but not ulcerative colitis.…”

“…18 An association between MSC and PROCR (p=7.43 × 10 −10 ) has been demonstrated using expression quantitative trait (eQTL) based analyses in melanocytes. 42 In addition, eQTL analyses with other skin datasets (skin un-exposed, skin not sun-exposed, and transformed skin fibroblasts) highlighted associations with both PROCR (not sun-exposed: p=9.02 × 10 −21 ) and MMP24 (not sun-exposed: p=2.82 × 10-7; sun-exposed: 2.31 × 10 −15 ). 42 PROCR is also referred to as EPCR or endothelial cell protein C receptor.…”

Analysis of risk allele frequencies of single nucleotide polymorphisms related to open-angle glaucoma in different ethnic groups

“…A recent study on multi-trait analysis of glaucoma used polygenic prediction for glaucoma progression in early manifest glaucoma cases and surgical intervention in advanced glaucoma cases, which could facilitate the development of a personalized approach for treatment [ 39 ]. In addition, another study showed that the association of polygenic risk score with IOP improved the prediction of OAG [ 40 ].…”

Genetic correlation and causality of cancers and Parkinson’s disease

“…Additionally, we contacted authors and requested for full summary statistics. Overall, we were able to collect full summary statistics for melanoma, 13 breast, 14 prostate, 15 endometrial 16 and keratinocytes cancers (basal cell carcinoma and squamous cell carcinoma). 17 Keratinocytes cancer summary statistics include meta-analysis of QSkin, eMERGE and UK Biobank (UKB) cohorts with a total of 28,218 cases and 353,855 controls.…”

“…We then selected the most recent available GWAS for each cancer, with a minimum of 1000 cases and at least the same number of controls of European ancestry. Additionally, recent GWASs on melanoma 13 and combined analysis of keratinocyte cancers 17 were added as they were not available in the GWAS catalog. Fifteen studies were selected for this part of the analysis (Supplementary Table 1) .…”