Abstract
Pigmentation of the skin, hair, and eyes varies both within and between human populations. Identifying the genes and alleles underlying this variation has been the goal of many candidate gene and several genome-wide association studies (GWAS). Most GWAS for pigmentary traits to date have been based on subjective phenotypes using categorical scales. But skin, hair, and eye pigmentation vary continuously. Here, we seek to characterize quantitative variation in these traits objectively and accurately and to determine their genetic basis. Objective and quantitative measures of skin, hair, and eye color were made using reflectance or digital spectroscopy in Europeans from Ireland, Poland, Italy, and Portugal. A GWAS was conducted for the three quantitative pigmentation phenotypes in 176 women across 313,763 SNP loci, and replication of the most significant associations was attempted in a sample of 294 European men and women from the same countries. We find that the pigmentation phenotypes are highly stratified along axes of European genetic differentiation. The country of sampling explains approximately 35% of the variation in skin pigmentation, 31% of the variation in hair pigmentation, and 40% of the variation in eye pigmentation. All three quantitative phenotypes are correlated with each other. In our two-stage association study, we reproduce the association of rs1667394 at the OCA2/HERC2 locus with eye color but we do not identify new genetic determinants of skin and hair pigmentation supporting the lack of major genes affecting skin and hair color variation within Europe and suggesting that not only careful phenotyping but also larger cohorts are required to understand the genetic architecture of these complex quantitative traits. Interestingly, we also see that in each of these four populations, men are more lightly pigmented in the unexposed skin of the inner arm than women, a fact that is underappreciated and may vary across the world.
Highlights
Human pigmentation of the skin, hair, and eyes varies worldwide
Using a Bonferroni correction per phenotype to set the significance threshold for the replication at 5% (p,2.461023 for skin, p,1.961023 for hair, and p,1.561023 for eye pigmentation), we find that five single nucleotide polymorphisms (SNPs) at the OCA2/HERC2 locus are reproducibly associated with eye pigmentation
Objective and quantitative phenotyping has the potential to improve the power to detect a genetic effect compared to genome-wide association studies (GWAS) based on subjective categorical phenotypes, but due to small sample size our study was only sufficiently powered to identify the major genetic effect of the HERC2/OCA2 locus on eye color
Summary
Human pigmentation of the skin, hair, and eyes varies worldwide. Skin pigmentation forms a gradient correlated with latitude, and variation in hair and eye color is extensive in Europe (reviewed in [1]). The use of categories necessarily results in a loss of information, leading to a loss of statistical power to detect genetic effects This was demonstrated in one study of eye color by Liu et al [11] who obtained both subjective categorical measures of eye color and objectively quantified eye color from digital photographs. To more comprehensively characterize skin, hair, and eye pigmentation in Europeans, we obtained both subjective categorical and objective quantitative measurements of skin, hair, and eye color in participants from four European countries: Ireland, Poland, Italy, and Portugal These countries, located near the geographical extremes of Europe, were chosen to capture a large fraction of European phenotypic variation. We studied the distributions and the correlations of the quantitative pigmentation phenotypes within and among these European countries and between the sexes, compared them to subjective self-assessments of pigmentation, and conducted a GWAS for each quantitative trait
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