A large-scale genome-wide association meta-analysis for nevus count provides direct insights into the genetics of melanoma

Abstract A greater understanding of the biology of nevi will provide insights into the etiology of melanoma. Our large-scale meta-analysis of 14 nevus genome-wide association studies (GWAS) includes 85,965 individuals of European ancestry. We identify 29 nevus-associated loci ( p < 5 × 10 -8 ), of which 24 have not been previously reported in a GWAS conducted for nevus count alone. We further identify 255 candidate genes for nevus loci, including SIKE1 which is involved in immune response regulation. This is of interest because immune response regulation influences the formation of nevi and melanoma susceptibility. Gene-set enrichment analyses prioritise immune response-related pathways and cancers that do not have a pigmentation component (e.g. breast, prostate, and glioma). This suggests that the biology underlying nevus count captures risk pathways beyond pigmentation that are relevant to melanoma. In sex-specific analyses, we observe higher total-body nevus count in females than in males, however the genetic architecture is largely shared (genetic correlation = 0.863, 95% CI = 0.453 – 1.273), indicating the difference may be influenced by environmental and behavioural factors rather than genetics. A nevus polygenic risk score explains 5% of the variance in nevus count, indicating its potential to enhance melanoma risk prediction.