Facial pigmented spots are a common skin aging feature, but genetic predisposition has yet to be thoroughly investigated. We conducted a genome-wide association study for pigmented spots in 2,844 Dutch Europeans from the Rotterdam Study (mean age: 66.9±8.0 years; 47% male). Using semi-automated image analysis of high-resolution digital facial photographs, facial pigmented spots were quantified as the percentage of affected skin area (mean women: 2.0% ±0.9, men: 0.9% ±0.6). We identified genome-wide significant association with pigmented spots at three genetic loci: IRF4 (rs12203592, P=1.8 × 10 -27), MC1R (compound heterozygosity score, P=2.3 × 10 -24), and RALY/ASIP (rs6059655, P=1.9 × 10 -9). In addition, after adjustment for the other three top-associated loci the BNC2 locus demonstrated significant association (rs62543565, P=2.3 × 10 -8). The association signals observed at all four loci were successfully replicated (P<0.05) in an independent Dutch cohort (Leiden Longevity Study n=599). Although the four genes have previously been associated with skin color variation and skin cancer risk, all association signals remained highly significant (P<2 × 10 -8) when conditioning the association analyses on skin color. We conclude that genetic variations in IRF4, MC1R, RALY/ASIP, and BNC2 contribute to the acquired amount of facial pigmented spots during aging, through pathways independent of the basal melanin production.

Additional Metadata
Persistent URL dx.doi.org/10.1038/jid.2015.62, hdl.handle.net/1765/84736
Journal The Journal of Investigative Dermatology
Grant This work was funded by the European Commission 7th Framework Programme; grant id fp7/259679 - Integrated research on DEvelopmental determinants of Aging and Longevity (IDEAL)
Jacobs, L.C, Hamer, M.A, Gunn, D.A, Deelen, J, Lall, J.S, van Heemst, D, … Nijsten, T.E.C. (2015). A genome-wide association study identifies the skin color genes IRF4, MC1R, ASIP, and BNC2 influencing facial pigmented spots. The Journal of Investigative Dermatology, 135(7), 1735–1742. doi:10.1038/jid.2015.62