A scan for genetic determinants of human hair morphology: EDAR is associated with Asian hair thickness

Abstract

Hair morphology is one of the most differentiated traits among human populations. However, genetic backgrounds of hair morphological differences among populations have not been clarified yet. In addition, little is known about the evolutionary forces that have acted on hair morphology. To identify hair morphology-determining genes, the levels of local genetic differentiation in 170 genes that are related to hair morphogenesis were evaluated by using data from the International HapMap project. Among highly differentiated genes, ectodysplasin A receptor (EDAR) harboring an Asian-specific non-synonymous single nucleotide polymorphism (1540T/C, 370Val/Ala) was identified as a strong candidate. Association studies between genotypes and hair morphology revealed that the Asian-specific 1540C allele is associated with increase in hair thickness. Reporter gene assays suggested that 1540T/C affects the activity of the downstream transcription factor NF-kappaB. It was inferred from geographic distribution of 1540T/C and the long-range haplotype test that 1540C arose after the divergence of Asians from Europeans and its frequency has rapidly increased in East Asian populations. These findings lead us to conclude that EDAR is a major genetic determinant of Asian hair thickness and the 1540C allele spread through Asian populations due to recent positive selection.

Effects of an Asian-specific nonsynonymous EDAR variant on multiple dental traits

“…3 These are partly consistent with a very low frequency or the absence of the EDAR 370A allele in European and North African populations. 15,30,32 However, as the 370A allele is also rare in Subsaharan Africans, there may be other genetic factors that affect their development of hypoconulids. As EDAR variants explained a small part of the variation in the presence/absence of hypoconulid in our study, it is indispensable to identify other genetic factors associated with this trait.…”

“…This polymorphism has also been reported to have an association with morphological variation in human hair. 15,16 EDAR encodes a receptor for ectodysplasin A (EDA), a soluble ligand, and it is a member of the tumor necrosis factor receptor family. 17,18 In humans, loss-of-function mutations of this gene result in hypohidrotic ectodermal dysplasia (MIM 129490, 224900 and 305100), which is a genetic disorder that results in congenital defects in tissues and structures of ectodermal origin such as teeth, nails, sweat glands and hair.…”

FGFR2 is associated with hair thickness in Asian populations

“…16 They also harbored SNPs with high population differentiation. 2,7,10 Especially, rs1385699 in EDA2R is a nonsynonymous SNP with high population differentiation, in which the derived allele of rs1385699 was not observed in YRI, whereas it reached the population frequency of 79.8 and 100.0% in CEU and CHB+JPT, respectively. 7 Although rs1385699 in EDA2R is a promising candidate for the hair morphology-determining gene, the association cannot be tested because of a low minor allele frequency in the studied Asian populations.…”

“…2 Of these genes, we subjected LEF1, MSX2, DLL1, EGFR, CUTL1, NOTCH1, FGFR2, KRT6IRS, GPC5, AKT1, MYO5A, TGM3, EDA2R and EDA, which are highly differentiated between HapMap-CHB+JPT and other HapMap populations (YRI and CEU). For ectodysplasin A2 receptor (EDA2R), a nonsynonymous SNP (rs1385699) was genotyped, because rs1385699 was recently reported to be involved in androgenetic alopecia.…”

“…Among these candidate genes, a nonsynonymous single nucleotide polymorphism (SNP) in ectodysplasin A receptor (EDAR), EDAR 1540T/C (rs3827760), which is highly differentiated between Asian (HapMap-CHB+JPT) and other populations (YRI and CEU), was found to be strongly associated with hair fiber thickness. 2,3 In addition, the chromosomal region of the EDAR gene showed a strong signature of recent positive selection in East Asian populations 2,[4][5][6][7][8][9] These results led to the conclusion that EDAR is a major genetic determinant of Asian hair thickness and is likely to play an important role in adaptation to the local environments of East Asia.…”