Melanocytic nevi, also called moles, are small pigmented skin lesions composed of a collection of melanocytes. Melanoma originates from melanocytes and can develop de novo or arise from an existing mole. The number of melanocytic nevi is a strong risk factor for melanoma. Therefore, identifying more genes associated with nevi should provide new insights into melanoma causality and risk assessment.
Although, nevus count has high heritability (60% to 70% in twins), only a few genetic loci have been identified through genome-wide association studies (GWAS) to date. Here, we report the largest ever GWAS meta-analysis for nevus count, combining previously published data with three new GWAS from QSkin Sun and Health Study phases I and II and the Australian Genetics of Depression Study. The new GWAS adds about 33,000 individuals with similar measures of whole-body nevus count, increasing the sample size to over 85,000.
We identified 28 nevus count loci, of which 23 were not previously reported for mole count alone. We found previously unknown candidate genes including strong gene mapping evidence for SIKE1 which is involved in immune response regulation. Pathway analysis found some of the new risk genes related to cancers that do not have a pigmentation component (e.g., breast, prostate and glioma), indicating that analysing nevus count can identify biological pathways relevant to melanoma that fall outside of known risk pathways. Our findings provide new insights into the genes and pathways critical in nevus development.