Mangantig, ErnestMacGregor , StuartIles, Mark M.Scolyer, Richard A.Cust, Anne EHayward, Nicholas K.Montgomery, Grant W.Duffy, David LThompson, John F.Henders, AnjaliMann, Graham2022-10-272022-10-270964-6906http://hdl.handle.net/1885/276214Germline genetic variants have been identified, which predispose individuals and families to develop melanoma. Tumor thickness is the strongest predictor of outcome for clinically localized primary melanoma patients. We sought to determine whether there is a heritable genetic contribution to variation in tumor thickness. If confirmed, this will justify the search for specific genetic variants influencing tumor thickness. To address this, we estimated the proportion of variation in tumor thickness attributable to genome-wide genetic variation (variant-based heritability) using unrelated patients with measured primary cutaneous melanoma thickness. As a secondary analysis, we conducted a genome-wide association study (GWAS) of tumor thickness. The analyses utilized 10 604 individuals with primary cutaneous melanoma drawn from nine GWAS datasets from eight cohorts recruited from the general population, primary care and melanoma treatment centers. Following quality control and filtering to unrelated individuals with study phenotypes, 8125 patients were used in the primary analysis to test whether tumor thickness is heritable. An expanded set of 8505 individuals (47.6% female) were analyzed for the secondary GWAS meta-analysis. Analyses were adjusted for participant age, sex, cohort and ancestry. We found that 26.6% (SE 11.9%, P = 0.0128) of variation in tumor thickness is attributable to genome-wide genetic variation. While requiring replication, a chromosome 11 locus was associated (P < 5 × 10-8) with tumor thickness. Our work indicates that sufficiently large datasets will enable the discovery of genetic variants associated with greater tumor thickness, and this will lead to the identification of host biological processes influencing melanoma growth and invasion.E.M. was supported by the Malaysian Ministry of Higher Education and Universiti Sains Malaysia to study for a PhD at the University of Leeds. A.E.C. was supported by a National Health and Medical Research Council (NHMRC) of Australia Career Development Fellowship (1147843). K.K. was supported by an NHMRC Career Development Fellowship (1125290). M.M.I. was supported by Cancer Research UK (c588/a19167) and the NIH (ca083115). R.A.S. and G.V.L. are supported by NHMRC Practitioner Fellowships; R.A.S. and J.F.T. also acknowledge support from an NHMRC program grant. D.C.W., S.M. and N.K.H were supported by NHMRC Research Fellowships (1058522, 1155413, 1154543 and 1117663). We thank Nicholas G. Martin for assistance with access to data from the Q-MEGA cohort and with manuscript writing. This work was conducted using the UK Biobank Resource (application number 25331).application/pdfen-AU© The Author(s) 2020. Published by Oxford University Press.https://creativecommons.org/licenses/by-nc/4.0/202010.1093/hmg/ddaa2222021-11-28Creative Commons Attribution Non-Commercial License