Poster Presentation GENEMAPPERS 2024

Insights into General and Sex-specific Genetic Effects on Nevus Count (#71)

Shanika Jayasinghe 1 2 , Stuart MacGregor 1 2 , Gu Zu 1 , Nirmala Pandeya 1 3 , Catherine Olsen 1 4 , Scott Gordon 1 , Penelope Lind 1 4 , Nick Martin 1 , Sarah Medland 1 5 , David Whiteman 1 , David Duffy 1 6 , Matthew Law 1 2 7
  1. QIMR Berghofer, Herston, QLD, Australia
  2. Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
  3. School of Public Health, University of Queensland, Brisbane, Australia
  4. School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD , Australia
  5. School of Psychology and Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
  6. Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia
  7. Faculty of Health, Queensland University of Technology (QUT), Brisbane, Australia

Moles or melanocytic nevi are benign skin lesions composed of melanocytes. Melanocytic nevi count is the strongest independent risk factor for melanoma and shares multiple genetic and environmental influences with melanoma. Parallel to the sex difference in melanoma incidence, nevus count also varies according to sex at different body sites. Therefore, investigating genetic influence on nevus count in the general population, and within each sex separately, will provide new insights into melanoma. 

Nevus count has high heritability, but only a few genetic loci have been identified through genome-wide association studies (GWAS) thus far. In this study, we present the largest GWAS meta-analysis for nevus count to date, leveraging data from previous studies and integrating three new GWAS datasets from the QSkin Sun and Health Study phases I and II, along with the Australian Genetics of Depression Study. This comprehensive approach increased the sample size to over 85,000 individuals, enhancing statistical power. Furthermore, we conducted a sex-specific GWAS meta-analysis in the newly integrated datasets. 

Overall, the nevus GWAS meta-analysis identified 28 loci associated with nevus count, 23 of which had not been previously reported solely for mole count. Our analysis identified previously unknown candidate genes, including SIKE1 at chromosome 1 which is involved in immune response regulation. Gene-set enrichment analysis highlighted pathways related to non-pigmentation-related cancers such as breast, prostate, and glioma, indicating the possibility of finding biological pathways relevant to melanoma beyond known risk factors like skin colour. Our sex-specific analysis identified minimal differences in effect sizes between the sexes with a genetic correlation of 0.86 (0.21) between sexes, indicating no strong evidence for sex-specific genetic differences in nevus count. In conclusion, our study provides new insights into the genetic and pathway mechanisms critical in nevus development, offering valuable implications for melanoma risk assessment.