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.

A Fast and Accurate Algorithm to Test for Binary Phenotypes and Its Application to PheWAS

“…In the analysis of skin cancer, variants in or near IRF4 (MIM: 601900), MC1R (MIM: 155555), RALY (MIM: 614663), and SLC45A2 (MIM: 606202) were significant at a ¼ 5 3 10 À8 , and all four of these genes were previously identified as associated with pigmentation traits and skin cancers. [31][32][33][34][35][36] In the other traits, variants in TCF7L2 (MIM:…”

“…Zhang et al 31 Sulem et al, 32 Jacobs et al, 33 and Liu et al 34 5:33951693 rs16891982 SLC45A2 C>G 0.038 7 3 10…”

The genetic basis of sunlight sensitivity and melanoma-risk pigmentation phenotypes: The role of sex-specific genetic effects, 3' untranslated regions and melanoma susceptibility genes

“…Loss-of-function MC1R alleles has been associated with the presence of solar lentigines, suggesting that melanocytes with reduced MC1R activity are expected to form these benign hyperpigmented lesions (37,97). Genetic variants in the SLC45A2 gene have also been found to be implicated in solar lentigines development (98), although this correlation was not found in a GWAS study using Caucasian individuals (30). This high-powered GWAS study demonstrated significant associations between variants in four pigmentation-related genes (IRF4, MC1R, ASIP and BNC2) and facial pigmented spots, including solar lentigines among others (30).…”

“…Furthermore, Jacobs and cols. (2015) showed that females presented a much higher prevalence of facial sun spots than males, suggesting that females are more severely affected by sun exposure than males independently of genotype (30). These differences could be the result of socio-cultural reasons, as males tend to spend more time outdoors; physiological reasons, as males have thicker skin and increased number of blood vessels; differential tanning, as no sex difference in basal skin pigmentation has been shown; and hormonal factors, as oestrogens stimulate pigmentation while androgens have an inhibitory effect on melanocytes (61,87).…”

“…In humans, variants in BNC2 have been associated with freckling (74), and with skin colour (75). Recently, a polymorphism (rs62543565*C) located 30 kb upstream from this gene has been significantly associated with facial pigmented spots independently of skin colour (30).…”