title: A Genome-Wide Association Study Identifies the Skin Color Genes IRF4, MC1R, ASIP, and BNC2 Influencing Facial Pigmented Spots.
abstract: 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.
authors.affiliation: Department of Dermatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.
authors.forename: Leonie C
authors.initials: LC
authors.lastname: Jacobs
authors.affiliation: Department of Dermatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.
authors.forename: Merel A
authors.initials: MA
authors.lastname: Hamer
authors.affiliation: Unilever, R&D, Colworth Science Park, Sharnbrook, Bedfordshire, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Gunn
authors.affiliation: Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands; Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: Deelen
authors.affiliation: Unilever, R&D, Colworth Science Park, Sharnbrook, Bedfordshire, UK.
authors.forename: Jaspal S
authors.initials: JS
authors.lastname: Lall
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Diana
authors.initials: D
authors.lastname: van Heemst
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hae-Won
authors.initials: HW
authors.lastname: Uh
authors.affiliation: Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands; Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Dermatology Centre, Salford Royal NHS Foundation Trust, University of Manchester, Salford, UK.
authors.forename: Christopher E M
authors.initials: CEM
authors.lastname: Griffiths
authors.affiliation: Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands; Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: Beekman
authors.affiliation: Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands; Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kayser
authors.affiliation: Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands. Electronic address: t.nijsten@erasmusmc.nl.
authors.forename: Tamar
authors.initials: T
authors.lastname: Nijsten
mesh_terms: D054366:Agouti Signaling Protein / Q000235:genetics*; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005148:Facial Dermatoses / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D055106:Genome-Wide Association Study; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008297:Male; D008548:Melanosis / Q000235:genetics; D008875:Middle Aged; D009426:Netherlands; D009508:Nevus, Pigmented / Q000235:genetics; D010641:Phenotype; D010781:Photography; D011446:Prospective Studies; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D012680:Sensitivity and Specificity; D012878:Skin Neoplasms / Q000235:genetics; D012880:Skin Pigmentation / Q000235:genetics*; D000099218:Interferon Regulatory Factor-4
chemical_list: D054366:Agouti Signaling Protein; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D044102:Receptor, Melanocortin, Type 1; D000099218:Interferon Regulatory Factor-4; C515182:ASIP protein, human; C484527:BNC2 protein, human