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Genome-Wide Study Uncovers Variants Explaining Majority of SNP Heritability of Red Hair

\NEW YORK (GenomeWeb) – Researchers have uncovered additional variants in the MC1R gene, as well as eight variants in other genes, that contribute to an individual's chances of having red hair.

Red hair had previously been linked to coding variations within the MC1R gene, which encodes a G-protein-coupled receptor that is expressed on the surface of skin and hair melanocytes. However, these MC1R variants are only partially penetrant, suggesting a role for other genetic factors in determining red hair.

A University of Oxford-led team conducted a genome-wide analysis of hair color using data from about 350,000 individuals in the UK Biobank, more than 15,700 of whom have red hair. As they reported yesterday in Nature Communications, the researchers uncovered additional MC1R variants as well as other gene variants that contribute to red hair, which all together account for about 90 percent of the SNP heritability. The researchers also linked more than 200 variants to blond hair, and suggested that there's a continuum from black to brown to blond hair based on which of those 200 variants a person has.

"We are very pleased that this work has unraveled most of the genetic variation contributing to differences in hair color among people," co-author Albert Tenesa from the University of Edinburgh said in a statement.

The genome-wide association study compared people with red hair to those with black or brown hair from the UK Biobank. This UK Biobank cohort included 343,234 participants of white British ethnicity who answered a question about their natural hair color.

As expected, the strongest association was near the MC1R gene on chromosome 16. Through stepwise conditional association testing, they identify 31 additional signals in this region, 10 of which they could directly attribute to amino acid changes, nonsense, or frameshift mutations in the MC1R coding region. These include two missense mutations that were not linked to red hair before.

Outside the MC1R region, the researchers uncovered eight additional associations that reached genome-wide significance with red hair. These include a variant near POMC, one in RALY, another in HERC2, and one in TSPAN10. POMC encodes α-MSH — an MC1R agonist — while RALY is located near ASIP, which encodes the inverse agonist of MC1R, the researchers said. They also noted epistatic interactions between MC1R alleles and other loci, including in the ASIP and HERC2/OCA3 regions.

Meanwhile, the researchers performed a GWAS comparing blond hair to a combined group of individuals with brown and black hair and found more than 200 variants associated with blond hair, including pigmentation-linked variants affecting SLC24A2, TYR, and MC1R. Although 93 percent of people with red hair harbor two MC1R variants, only 15 percent of people with two MC1R variants have red hair, the researchers noted, adding that most people with two MC1R variants have light brown or blond hair, the researchers said.

They likewise conducted a GWAS of brown versus black hair and found 56 variants, 28 of which overlapped with blond hair-linked variants with the same direction of effect.

The researchers developed a polygenic phenotype score for hair color using the variants that reached genome-wide significance in their analysis of blond versus brown and black hair color. The results showed that self-reported hair color appeared to fall along a linear continuum from black to dark brown to light brown to blond hair, a finding the team confirmed in two other groups of individuals.

In addition, the investigators estimated that the loci they identified explain about 90 percent of the SNP heritability of red hair. Similarly, for blond hair and brown hair, the loci they identified account for 73 percent and 47 percent of SNP heritability, respectively.