Deterioration in the fine lines on the skin has been associated with solar keratoses and skin cancer. Previously we have reported that at age 12 additive gene effects explain 86% of the variation skin patterning as assessed by the six-point Beagley-Gibson scale. Heritability estimates decrease with age with non-additive gene effects explaining 62% of the variation in adults. Here, we present results of a genome-wide association study (GWAS) of skin pattern in 2550 adolescent twins and siblings from 1063 families. Two single nucleotide variants reached genome wide significance, on in the Melanocortin Receptor 1 gene (MC1R) on chromosome 16 with a p = 3.98 x 10-8. A number of functional alleles are known to exist in MC1R which strongly influence the chance of red hair and pale pigmentation; together these MC1R red hair alleles explain 4.23% of skin pattern variance. A SNP in interferon regulatory factor 4 gene (IRF4) on chromosome 6 achieved a GWAS p=2.95 x 10-8 and explains 1.53% of skin pattern variance. Red hair alleles in MC1R were also significantly associated with the number of sunburns and with sun-protective behaviours, providing evidence that genetic variants may interact with a complex trait by modulating environmental exposure.
It is reasonable to assume that a proportion of the near genome-wide significant SNPs resulting from a GWAS are associated with the studied trait, and fail to reach significance due to lower effect size or chance. For example an additional locus on chromosome 4 is of interest since includes the epidermal growth factor gene EGF (GWAS p= 2 x 10-6 1.14% of variance). To explore variants that were approaching genome wide significance further, we utilise gene and pathway based approaches.