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

Leonie Jacobs, Merel Hamer, DA Gunn, J Deelen, JS Lall, D van Heemst, HW Uh, Bert Hofman, André Uitterlinden, CEM Griffiths, M Beekman, PE (Eline) Slagboom, Manfred Kayser, Fan Liu, Tamar Nijsten

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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.
Original languageUndefined/Unknown
Pages (from-to)1735-1742
Number of pages8
JournalJournal of Investigative Dermatology
Issue number7
Publication statusPublished - 2015

Research programs

  • EMC MGC-02-26-01
  • EMC MM-01-39-09-A
  • EMC MM-03-61-05-A
  • EMC NIHES-01-64-01

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