A Genome-Wide Association Study Identifies the Skin Color Genes IRF4, MC1R, ASIP, and BNC2 Influencing Facial Pigmented Spots

摘要

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 x 10(-27)), MC1R (compound heterozygosity score, P = 2.3 x 10(-24)), and RALY/ASIP (rs6059655, P = 1.9 x 10(-9)). In addition, after adjustment for the other three top-associated loci the BNC2 locus demonstrated significant association (rs62543565, P= 2.3 x 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 x 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.