Abstract
Hair colour is a polygenic phenotype that results from differences in the amount and ratio of melanins located in the hair bulb. Genome-wide association studies (GWAS) have identified many loci involved in the pigmentation pathway affecting hair colour. However, most of the associated loci overlap non-protein coding regions and many of the molecular mechanisms underlying pigmentation variation are still not understood. Here, we conduct GWAS meta-analyses of hair colour in a Canadian cohort of 12,741 individuals of European ancestry. By performing fine-mapping analyses we identify candidate causal variants in pigmentation loci associated with blonde, red and brown hair colour. Additionally, we observe colocalization of several GWAS hits with expression and methylation quantitative trait loci (QTLs) of cultured melanocytes. Finally, transcriptome-wide association studies (TWAS) further nominate the expression of EDNRB and CDK10 as significantly associated with hair colour. Our results provide insights on the mechanisms regulating pigmentation biology in humans.
Highlights
Hair colour is a polygenic phenotype that results from differences in the amount and ratio of melanins located in the hair bulb
Previous studies have identified the presence of allelic heterogeneity, in which different variants within a single gene are associated with pigmentation variation in different populations (e.g., MFSD12, OCA2)[5,13,14], as well as the effect of multiple independent variants on the same locus associated with a diverse range of pigmentation tones within populations (e.g., HERC2/OCA2, MC1R, GRM5/ TYR)[5,15,16,17,18,19]
Hair colour is a quantitative phenotype that results from differences in the amount and ratio of eumelanin and pheomelanin synthesised in melanocytes located in the hair bulb, which migrate to the hair shaft[28,29,30,31]
Summary
Hair colour is a polygenic phenotype that results from differences in the amount and ratio of melanins located in the hair bulb. Morgan and colleagues provided a detailed analysis of the loci associated with red hair colour, including penetrance and interactions among single-nucleotide polymorphisms (SNPs), offering insights on the genetic complexity of this hair colour tone[33] In spite of these advances, for most of the hair pigmentation-associated loci, the causal variants and the molecular mechanisms underlying pigmentation variation remain to be identified[34]. This is a challenging task, given that most of the top SNPs associated with hair colour are located in nonprotein-coding regions of the genome, with no obvious or direct function on the trait, hinting to a regulatory function
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