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

Fan Liu,Mijke Visser,Lakshmi Chaitanya,Massimo Mangino,Nicholas G Martin,Fernando Rivadeneira,Timothy D Spector,Leonie C Jacobs,Wilfred F J Van Ijcken,Pirro G Hysi,Kaiyin Zhong,Anjali K Henders,David L Duffy,Gu Zhu,Albert Hofman,Andreas Wollstein,Manfred Kayser,Oscar Lao,Daniel Glass,André G Uitterlinden,Susan Walsh,Richard A Sturm,Grant W Montgomery,Véronique Bataille ,Robert-Jan Palstra ,Tamar Nijsten

doi:10.1007/s00439-015-1559-0

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-015-1559-0) contains supplementary material, which is available to authorized users.

Highlights

While the principal genes influencing eye and hair color are largely identified, current knowledge on the genetic basis of skin color variation is still limited (Liu et al 2013)
To search for additional DNA variants involved in European skin color variation, the International Visible Trait Genetics (VisiGen) Consortium conducted a series of genome-wide association studies (GWASs) followed by a replication analysis in a total of 17,262 Europeans (Table S1) from three discovery cohorts including: the Rotterdam Study (RS) n = 5857 from the Netherlands, the Brisbane Twin Nevus Study (BTNS) n = 3459 of European descent from Australia, and the TwinsUK study, n = 2668 from the United Kingdom
A total of five distinct genomic regions were identified that harbored DNA variants associated with skin color at the genome-wide significant level (p value

Summary

Introduction

While the principal genes influencing eye and hair color are largely identified, current knowledge on the genetic basis of skin color variation is still limited (Liu et al 2013).

Results

Conclusion