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

Liu F, Visser M, Duffy DL, Hysi PG, Jacobs LC, Lao O, Zhong K, Walsh S, Chaitanya L, Wollstein A, Zhu G, Montgomery GW, Henders AK, Mangino M, Glass D, Bataille V, Sturm RA, Rivadeneira F, Hofman A, van IJcken WF, Uitterlinden AG, Palstra RJ, Spector TD, Martin NG, Nijsten TE, Kayser M - Hum. Genet. (2015)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands, f.liu@erasmusmc.nl.

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.

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Related in: MedlinePlus

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)
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Fig1: 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)

Mentions: For four of the five highlighted genomic regions, i.e., 5p13.2(Fig. 1a), 6p25.3 (Fig. 1b), 15q13.1 (Fig. 1c), and 16q24.3 (Fig. 1d), the genes responsible for the noted skin color association signals are well documented for their involvement in human pigmentation traits, i.e., SLC45A2, IRF4, OCA2/HERC2, and MC1R, respectively (Liu et al. 2013). However, from previous studies it is much less clear which gene(s) in the 20q11.22 region may functionally explain the observed SNP association with skin color (Liu et al. 2013). Unlike the other four regions, the top-associated SNP (rs6059655) in 20q11.22 (Fig. 1e) was genome-wide significant only for quantitative skin color saturation (p = 6.36 × 10−13 in RS), and was less significant for PSD (p value = 4.22 × 10−6 in RS; p value = 8.58 × 10−6 in BTNS) and FPS (p value = 1.27 × 10−7 in TwinsUK, Table S2). Among all other 20q11 SNPs with p values smaller than 1 × 10−6, rs1885120 within MYH7B and rs910873 within PIGU have been previously associated with melanoma risk (Brown et al. 2008), and an intergenic SNP rs4911466 has been associated with sun burning, freckling, red hair, and skin sensitivity to sun (Sulem et al. 2008). The association signals noted at 20q11.22 span a large haplotype block of ~1.5 Mb containing 22 known genes, among which ASIP, a gene encoding the agouti signaling protein, is assumed to be involved in melanogenesis (Suzuki et al. 1997). However, variants from coding regions of ASIP may not explain the observed association as previously suggested (Sulem et al. 2008). The SNP rs6059655 in intron 8 of RALY is ~182 kBp (hg19) upstream of ASIP. All other SNPs in this region showing association signals (p value <1 × 10−6) with skin color phenotypes were in moderate or high linkage disequilibrium with rs6059655 (LD r2 > 0.4 in our European data). However, none of them displayed any significant independent association at the genome-wide level after conditioning for the rs6059655 genotype (all p values >0.001). Haplotype and SNP interaction analyses at 20q11 did not reveal more significant association signals for other SNPs than rs6059655 alone (Figure S3).Fig. 1


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

Liu F, Visser M, Duffy DL, Hysi PG, Jacobs LC, Lao O, Zhong K, Walsh S, Chaitanya L, Wollstein A, Zhu G, Montgomery GW, Henders AK, Mangino M, Glass D, Bataille V, Sturm RA, Rivadeneira F, Hofman A, van IJcken WF, Uitterlinden AG, Palstra RJ, Spector TD, Martin NG, Nijsten TE, Kayser M - Hum. Genet. (2015)

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)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig1: 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)
Mentions: For four of the five highlighted genomic regions, i.e., 5p13.2(Fig. 1a), 6p25.3 (Fig. 1b), 15q13.1 (Fig. 1c), and 16q24.3 (Fig. 1d), the genes responsible for the noted skin color association signals are well documented for their involvement in human pigmentation traits, i.e., SLC45A2, IRF4, OCA2/HERC2, and MC1R, respectively (Liu et al. 2013). However, from previous studies it is much less clear which gene(s) in the 20q11.22 region may functionally explain the observed SNP association with skin color (Liu et al. 2013). Unlike the other four regions, the top-associated SNP (rs6059655) in 20q11.22 (Fig. 1e) was genome-wide significant only for quantitative skin color saturation (p = 6.36 × 10−13 in RS), and was less significant for PSD (p value = 4.22 × 10−6 in RS; p value = 8.58 × 10−6 in BTNS) and FPS (p value = 1.27 × 10−7 in TwinsUK, Table S2). Among all other 20q11 SNPs with p values smaller than 1 × 10−6, rs1885120 within MYH7B and rs910873 within PIGU have been previously associated with melanoma risk (Brown et al. 2008), and an intergenic SNP rs4911466 has been associated with sun burning, freckling, red hair, and skin sensitivity to sun (Sulem et al. 2008). The association signals noted at 20q11.22 span a large haplotype block of ~1.5 Mb containing 22 known genes, among which ASIP, a gene encoding the agouti signaling protein, is assumed to be involved in melanogenesis (Suzuki et al. 1997). However, variants from coding regions of ASIP may not explain the observed association as previously suggested (Sulem et al. 2008). The SNP rs6059655 in intron 8 of RALY is ~182 kBp (hg19) upstream of ASIP. All other SNPs in this region showing association signals (p value <1 × 10−6) with skin color phenotypes were in moderate or high linkage disequilibrium with rs6059655 (LD r2 > 0.4 in our European data). However, none of them displayed any significant independent association at the genome-wide level after conditioning for the rs6059655 genotype (all p values >0.001). Haplotype and SNP interaction analyses at 20q11 did not reveal more significant association signals for other SNPs than rs6059655 alone (Figure S3).Fig. 1

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands, f.liu@erasmusmc.nl.

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.

Show MeSH
Related in: MedlinePlus