Genome-Wide Association Study of Nevus Count Reveals Opposing Effects of Genetic Loci Near IRF4 and MC1R on Flat Versus Raised Nevus Count in the Brisbane Twin Nevus Study: A Cross-Sectional Analysis.

Germline genetic variation can influence the number of nevi on the skin. However, nevi can be classified in many ways (e.g., by shape, size or evolution); little is known of how genetics influences the density of different nevus morphologies on the body. Here, we explore how germline genetics influences the density of flat, raised and atypical nevi, and identify which classification correlates most with genetic risk of melanoma. We estimate heritability and perform genome-wide association analysis of flat, raised, and atypical nevus count within the Brisbane Twin Nevus Study (N = 3862). We compare the effect estimates of genetic loci associated with each morphology. We also assess how well each morphology correlates with the genetic risk of melanoma using a polygenic risk score of melanoma. Heritability estimates revealed both unique and shared genetic effects between morphologies. We identified two loci near IRF4 and MC1R showing opposing effects on flat and raised nevus counts. Variation in raised nevus count showed the strongest correlation with melanoma risk using polygenic risk scores. Although some genetic effects are shared between nevus morphologies, they appear to be genetically distinct phenotypes. Given the opposing effects of IRF4 and MC1R on flat and raised nevus counts, future studies of nevus count should consider, where possible, analysing each nevus morphology separately as well as combined.