Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up

Abstract

In the International Visible Trait Genetics (VisiGen) Consortium, we investigated the genetics of human skin color by combining a series of genome-wide association studies (GWAS) in a total of 17,262 Europeans with functional follow-up of discovered loci. Our GWAS provide the first genome-wide significant evidence for chromosome 20q11.22 harboring the ASIP gene being explicitly associated with skin color in Europeans. In addition, genomic loci at 5p13.2 (SLC45A2), 6p25.3 (IRF4), 15q13.1 (HERC2/OCA2), and 16q24.3 (MC1R) were confirmed to be involved in skin coloration in Europeans. In follow-up gene expression and regulation studies of 22 genes in 20q11.22, we highlighted two novel genes EIF2S2 and GSS, serving as competing functional candidates in this region and providing future research lines. A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples (HGDP-CEPH) showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological investigations.

Fig. 1

Regional Manhattan plots for skin color phenotypes in the Rotterdam Study, the Brisbane Twin Nevus Study, and the TwinsUK study. a chromosome 5p13.2 (33.7–34.2 Mb) containing SLC45A2; b chromosome 6p25.3 (0.2–0.7 Mb) containing IRF4; c chromosome 15q13.1 (28.0–28.7 Mb) containing OCA2 and HERC2; d chromosome 16q24.3 (89.0–90.2 Mb) containing MC1R; and e a large region on chromosome 20q11.22 spanning ~1.5 Mb (32.3–34.0 Mb) containing ASIP. The −log10 p values of all SNPs are plotted against their physical positions (hg19). The blue horizontal line stands for the p value threshold of 5 × 10⁻⁸. p value dots are represented in colors and shapes indicating different phenotypes from different study cohorts (plink circle perceived skin darkness in BTNS, green triangles perceived skin darkness in RS, blue squares quantitative skin color saturation in RS, and purple pluses Fitzpatrick scales in TwinsUK). The physical positions of all known genes in the regions are aligned (color figure online)

Fig. 2

Expression of ASIP in full, dermal, and epidermal layers of skin. a Plot of eQTL analysis on ASIP, where expression of ASIP is strongly associated with pigmentation variants rs17305573, rs910873 and rs1885120 in skin full-layer biopsy samples. b ASIP is exclusively expressed in the dermal layer of skin, and not in the epidermal layer of skin (nd not detected). Samples derived from the dermal layer are denoted with ‘D’, samples derived from the epidermal layer are denoted with ‘E’. Sample 1 has the rs1885120-CC genotype, with a dark skin phenotype, sample 2 has the rs1885120-CC genotype, with a light skin phenotype, sample 3 has the rs1885120-CT genotype, with a light skin phenotype