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 study (GWAS) included 85,967 individuals of European ancestry. We identified 29 nevus-associated loci (p < 5×10−8), of which 24 were not previously reported in a GWAS conducted for nevus count alone. We further identified 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 prioritised 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. A nevus polygenic risk score explains 5% of the variance in nevus count, indicating its potential to enhance melanoma risk prediction. Competing Interest Statement The authors have declared no competing interest. Funding Statement Stuart MacGregor. is supported by an Investigator grant (2034568) from the Australian National Health and Medical Research Council (NHMRC). Mark M Iles is supported in part by the National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre (BRC) (NIHR203331). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Sarah E Medland is supported by NHMRC grants APP1172917 and APP2025674. Nicholas K Hayward is supported by the NHMRC (APP1195581), Jan Brown, the Buck Off Melanoma community and memorial donors honouring Nicola Laws. This work was conducted using the UK Biobank Resource (application number 25331). We acknowledge the contribution of the data from the published nevus meta-analysis in 2018 and the melanoma meta-analysis in 2020. All studies are forever grateful for the invaluable contributions of all research participants, their families, research nurses, research assistants, and support staff, whose dedication made this work possible. Please see supplementary notes for more details of acknowledgments and financial support for contributing studies. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Human Research Ethics Committee of QIMR Berghofer Medical Research Institute gave ethical approval for this work as well as the ethical approval for the QSkin Sun and Health Study (QSkin I: P1309 and P2034 and QSkin II: P3434) and Australian Genetics of Depression Study (AGDS: P2118). The Kidskin Young Adult Myopia Study (KYAMS) was approved by the Human Research Ethics Committees of the University of Western Australia (RA/4/1/6807). All study participants over 18 years provided written informed consent; for those under 18 years consent was obtained from parents. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data availability The summary data for the GWAS meta-analysis generated in this study is available on Zenodo [URL to be confirmed]. Individual-level data from UK Biobank was accessed under application number 25331. Access to UK Biobank data can be obtained by applying to UK Biobank (https://www.ukbiobank.ac.uk/). All other data supporting this study may be available to the corresponding authors upon request, subject to ethical and regulatory approval from the relevant institution.