![]() ![]() Furthermore, we identify eight additional variants that explain most of the SNP heritability of red hair, including variants at ASIP, where an eQTL shows epistatic interactions with the poorly penetrant MC1R variants. By performing genome-wide analyses across hair colours, we have discovered novel variation in and around MC1R that contributes to red hair. We report here the analysis of the majority of UK Biobank, a total of almost 350,000 subjects. This has the potential to mask associations due to differences in genetic architecture for separate categories of hair colour. This report, however, mostly considered hair colour as a single ordered variable including red hair. 15 analysed a subset of participants in a very large population health cohort of British individuals, UK Biobank, in addition to a similar number of individuals from 23andMe, totalling 290,891. However, during preparation of this manuscript a GWAS was reported identifying over 100 loci contributing to hair colour 15. Most of these genes have been previously described as causing coat colour variation in mice ( MC1R, ASIP, OCA2, SLC45A2, KITLG, TYR, TYRP1, EDNRB), zebrafish ( SLC24A5) and humans ( TPCN2, IRF4). ![]() Each of these studies identified between 4 and 8 genes, with a total of 11 genes associated with hair colour differences. Until recently, genome-wide association studies (GWAS) identified only a small number of loci associated with blonde hair, compared to black and brown 11, 12, 13, 14. Previous studies have defined a role for ASIP in red hair in humans, but its molecular basis is largely unknown 9, 10. Overexpression of ASIP, in mice for example, leads to synthesis of only yellow phaeomelanin, even in the presence of a functional MC1R and α-MSH 8. MC1R has a second ligand, an inverse agonist, agouti signalling protein (ASIP) 7. Loss of MC1R signalling in many vertebrate species results in the inability of the melanocytes to produce eumelanin that instead default to synthesising phaeomelanin, a red or yellow pigment. The cellular trafficking of melanosomes to keratinocytes in the hair follicle additionally gives colour to the growing hair. This is packaged into vesicles, termed melanosomes, for transport to epidermal keratinocytes where it provides protection against ultraviolet radiation. Binding of the MC1R cognate ligand, α-melanocyte stimulating hormone (α-MSH), induces a melanogenic cascade resulting in the production of dark eumelanin. MC1R is a G-protein-coupled receptor, expressed on the surface of skin and hair melanocytes. Other genetic factors must be interacting with MC1R to modify the penetrance of these variants. Less well known is the observation that most of these variants are only partially penetrant, and some of them have very low penetrance indeed 6. Red hair is well established as being associated with coding variation in the MC1R gene 4, 5. Several studies have examined the genetic basis of hair colour variation. Hair colour variation is partially correlated with skin and eye colour variation, reflecting differences in cellular interaction in different tissues 2, 3. It is thus an excellent model system to explore genetic and cellular interactions in development and homoeostasis. Furthermore, hair colour is largely determined by only a few well-characterised cell types: the melanocytes where the melanin pigment is made, the keratinocytes of the hair to which the pigment is transferred and fibroblasts of the dermal papilla, which signal to and regulate the melanocytes. Natural hair colour within European populations is strikingly variable and is a complex genetic trait that is impacted relatively little by known, non-genetic, factors 1.
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