Genome-Wide Association Studies of Quantitatively Measured Skin, Hair, and Eye Pigmentation in Four European Populations

May combine two claims.

Average skin pigmentation differs among countries, with the exception of the Poland vs. Portugal comparison.

“With the exception of the Poland vs. Portugal comparison, average skin pigmentation is also different among countries.”

May combine two claims.

For hair color, individuals reporting red hair have the lowest median M index (median M = 73), followed by blond (median M = 101) and then brown or black (median M = 124).

“individuals reporting red hair color have the lowest median M index (median M = 73), followed by blond (median M = 101) and then brown or black (median M = 124)”

May combine two claims.

Sex explains 10.3%, 0.0%, and 0.0% of the phenotypic variance in skin, hair, and eye pigmentation, respectively.

“explaining only 10.3%, 0.0%, and 0.0% of the phenotypic variance in skin, hair, and eye pigmentation, respectively”

May combine two claims.

Country of sampling explains approximately 35% of the variation in skin pigmentation, 31% in hair pigmentation, and 40% in eye pigmentation.

“The country of sampling explains approximately 35% of the variation in skin pigmentation, 31% of the variation in hair pigmentation, and 40% of the variation in eye pigmentation.”

• Also stated in: § Stratification of the Phenotypes · plain

  “Country of origin explains 35.3%, 30.8%, and 39.7% of the variation in the skin, hair, and eye pigmentation, respectively.”

May combine two claims.

Country explains 4.9% of the variance in height, while sex explains 45.8% of the variance in height.

“country explains only 4.9% of the variance in height, while sex explains 45.8% of the variance in height”

Probably not a substantial claim: may not pass S3 (load-bearing).

The C' score for eye pigmentation has a bimodal distribution (n = 468).

“The C’ score for eye pigmentation has a bimodal distribution (Figure 1E, n = 468).”

May combine two claims.

For eye pigmentation, the two modes of the C' distribution correspond to blue and brown eye color, while green and hazel eye color correspond to intermediate C' scores.

“the two modes of the C’ distribution correspond to blue and brown eye color, while green and hazel eye color correspond to intermediate C’ scores”

May combine two claims.

Hair pigmentation differs among all countries, most differentiated between Northern and Southern Europe.

“While hair pigmentation differs among all countries, it is most differentiated between Northern and Southern Europe”

May combine two claims.

The median C' scores for blue, green, hazel, and brown self-reported eye colors were 0.69, 1.55, 2.07, and 2.25, respectively.

“The median C’ scores for blue, green, hazel, and brown self-reported eye colors were 0.69, 1.55, 2.07, and 2.25, respectively.”

May combine two claims.

PC3 separates Portugal from Ireland and Italy, while Poland has more intermediary values on PC3.

“PC3 separates Portugal from Ireland and Italy, while Poland has more intermediary values on PC3”

May combine two claims.

Most participants cluster by country of sampling, while ten individuals are found between the clusters formed by each country.

“most participants cluster by country of sampling while ten individuals are found between the clusters formed by each country”

May combine two claims.

The derived allele frequency of the imputed rs12913832 is 0.90, 0.83, 0.59 and 0.44 and the genetic effect of rs12913832 explains 20%, 42%, 12%, and 33% of the variance in quantitative eye color in the GWAS sample from Ireland, Poland, Italy, and Portugal, respectively.

“The derived allele frequency of the imputed rs12913832 is 0.90, 0.83, 0.59 and 0.44 and the genetic effect of rs12913832 explains 20%, 42%, 12%, and 33% of the variance in quantitative eye color in our GWAS sample from Ireland, Poland, Italy, and Portugal, respectively.”

May combine two claims.

The two population-structure correction methods, country of sampling and genetic PCs, produce highly correlated test statistics and overlapping top association signals.

“The two methods produce highly correlated test statistics and overlapping top association signals (see Material and Methods)”

May combine two claims.

The five reproducibly associated SNPs are rs1667394, rs8039195, rs1635168, rs16950987, and rs8028689, spanning a 46kb interval.

“These five SNPs are rs1667394, rs8039195, rs1635168, rs16950987, and rs8028689. They span a 46kb interval.”

May combine two claims.

rs1667394 is located 186 kb 5′ of OCA2 first exon and within an HERC2 intron and is in linkage disequilibrium with the other four SNPs (r2 = 0.91, 0.46, 0.39, and 0.39 with rs8039195, rs1635168, rs16950987, and rs8028689, respectively in HapMap release 27 CEU).

“It is located 186 kb 5′ of OCA2 first exon and within an HERC2 intron and is in linkage disequilibrium (LD) with the other four SNPs (r2 = 0.91, 0.46, 0.39, and 0.39 with rs8039195, rs1635168, rs16950987, and rs8028689, respectively in HapMap release 27 CEU).”

May combine two claims.

Country of sampling explains 38.6%, 24.8%, and 34.5% of the variation in skin, hair, and eye pigmentation, respectively, in the same samples.

“Country of sampling explains a similarly large fraction of variation in the phenotypes of the same samples: 38.6%, 24.8% and 34.5% of the variation in skin, hair, and eye pigmentation respectively.”

May combine two claims.

The percent variance explained is greatest in Poland, where there is the largest variation in eye color.

“The percent variance explained is greatest in Poland, where there is the largest variation in eye color.”

May combine two claims.

While the study does not identify novel genetic determinants of pigmentation, it demonstrates the extensive stratification of pigmentary phenotypes in Europe along the major axes of genetic variation.

“While our study does not identify novel genetic determinants of pigmentation, it does demonstrate the extensive stratification of pigmentary phenotypes in Europe along the major axes of genetic variation.”

May combine two claims.

In the GWAS, the p-value for the association of hair pigmentation with imputed rs12913832 is 0.01, and after correcting for eye color, the p-value is 0.02.

“In our GWAS, the p-value for the association of hair pigmentation with imputed rs12913832 is 0.01. After correcting for eye color, the p-value is 0.02.”

May combine two claims.

rs1042602 is associated with freckles in Europeans but the study does not find evidence for its association with skin pigmentation (p = 0.3).

“It is associated with freckles in Europeans [13] but we do not find evidence for its association with skin pigmentation in our study (p = 0.3).”

• cites [13] P Sulem, 2007, Genetic determinants of hair, eye and skin pigmentation in Europeans, Nature genetics sourceNot checked yet

  Not checked in the free run.

May combine two claims.

rs183671 shows some evidence of association with skin pigmentation (p = 6×10−4, n = 289), and each copy of the derived allele lightens the skin by 1.2 M index units, further arguing for an effect of SLC45A2 on European skin pigmentation variation.

“We found that this SNP shows some evidence of association with skin pigmentation (p = 6×10−4, n = 289), and that each copy of the derived allele lightens the skin by 1.2 M index units, further arguing for an effect of SLC45A2 on European skin pigmentation variation.”

May combine two claims.

In this European sample, pigmentation phenotypes are mainly stratified by country, whereas height is mainly stratified by sex.

“in this European sample, pigmentation phenotypes are mainly stratified by country, whereas height is mainly stratified by sex”

Classified as probably not a substantial claim.

Replication of the most significant GWAS association signals was attempted in 294 individuals (104 Irish, 27 Polish, 64 Italian, and 99 Portuguese; 153 males and 141 females).

“Replication of the most significant GWAS association signals was attempted in 294 individuals (104 Irish, 27 Polish, 64 Italian, and 99 Portuguese; 153 males and 141 females)”

Probably not a substantial claim: may not pass S3 (load-bearing).

In total, 313,763 SNPs were analyzed in 176 individuals for the genome-wide association study.

“In total, 313,763 SNPs were analyzed in 176 individuals for the genome-wide association study (GWAS).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Empirical p-values were obtained by permuting the phenotypes within each country of sampling 10,000,000 times for all GWAS association signals with linear model p-value<10−4.

“empirical p-values were also obtained by permuting the phenotypes within each country of sampling 10,000,000 times for all GWAS association signals with linear model p-value<10−4”

Probably not a substantial claim: may not pass S3 (load-bearing).

An exact test of deviation from Hardy-Weinberg equilibrium was implemented for each SNP in the four population samples.

“an exact test of deviation from Hardy-Weinberg equilibrium (HWE) was implemented for each SNP in the four population samples”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

One individual with >10% missing data and three individuals that were genetic outliers in the population structure analyses were excluded from all analyses.

“One individual with >10% missing data and three individuals that were genetic outliers in the population structure analyses were also excluded from all analyses.”

May combine two claims.

The permuted p-values for the top hits of the skin (rs9809315), hair (rs262825), and eye pigmentation (rs1667394) GWAS were 1×10−7, 6.3×10−6, and <1×10−7, respectively.

“The permuted p-values for the top hits of the skin (rs9809315), hair (rs262825), and eye pigmentation (rs1667394) GWAS were 1×10−7, 6.3×10−6, and <1×10−7, respectively.”

Probably not a substantial claim: may not pass S3 (load-bearing).

SNPs with missing rate >10%, maf <0.01, and p-values<0.01 in at least two populations for a test of deviation from HWE were excluded.

“SNPs with missing rate >10%, maf <0.01, and p-values<0.01 in at least two populations for a test of deviation from HWE were excluded.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Principal components were calculated based on a set of 263,607 SNPs that had been subjected to higher quality control than the SNPs considered for the GWAS.

“Principal components were calculated based on a set of 263,607 SNPs that had been subjected to higher quality control than the SNPs considered for the GWAS.”

May combine two claims.

Known loci explain approximately 20-30% of the phenotypic variance for black to blond hair color and 40-60% for eye color in Europeans, with the remaining phenotypic variation unexplained.

“approximately 20–30% for black to blond hair color and 40–60% for eye color, the remaining phenotypic variation in these traits remains unexplained [8], [9], [11].”

• cites [8], [9], [11]Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The Pearson correlation between all-sample allele frequency in the GWAS and replication samples was high (r = 0.97).

“The Pearson correlation between all-sample allele frequency in the GWAS and replication samples was high (r = 0.97).”

May combine two claims.

The genomic control lambda factors for the skin, hair and eye pigmentation GWAS were each close to 1 and there was no systematic deviation from expectation in the Q-Q plots.

“The genomic control lambda factors for the skin, hair and eye pigmentation GWAS were each close to 1 and there was no systematic deviation from expectation (the diagonal) in the Q-Q plots.”

May combine two claims.

Three individuals, one recruited in Ireland and two in Portugal, were clearly outliers within their group by nearest neighbor analysis and were removed from all association testing.

“Three individuals, one recruited in Ireland and two in Portugal, were clearly outliers within their group (z score <−3 for first to fifth nearest neighbor). These individuals were removed from all association testing.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Variation between red and non-red hair color is explained by variation at MC1R and ASIP.

“between red and non-red hair color by variation at MC1R and ASIP (reviewed in [14])”

• cites [14] MR Gerstenblith, 2010, Genome-wide association studies of pigmentation and skin cancer: a review and meta-analysis, Pigment cell & melanoma research sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The alignment of the first two genetic PCs with geography and the clustering of individuals by European country are consistent with the results of a previous larger study of European genetic structure.

“The alignment of the first two genetic PCs with geography and the clustering of individuals by European country are consistent with the results of a previous larger study of European genetic structure [28].”

• cites [28] J Novembre, 2008, Genes mirror geography within Europe, Nature sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The strong linear relationship between global skin pigmentation variation and latitude/UV radiation levels is thought to result from UV-mediated vitamin D synthesis, folate photolysis, sunburn, and skin cancer.

“The strong linear relationship between global skin pigmentation variation and latitude/UV radiation levels is thought to result from UV-mediated vitamin D synthesis, folate photolysis, sunburn, and skin cancer [2]–[5].”

• cites [2]–[5]Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Two participants genotyped in duplicate showed good concordance of the genotypes (99.97% on average).

“two participants were genotyped in duplicate and showed good concordance of the genotypes (99.97% on average)”

May combine two claims. The quote only partly states this claim.

The GWAS p-values corrected for population structure by country of sampling and by the first three genetic PCs were similar; the Pearson correlation coefficients between the linear model t-statistics from the two GWAS results are 0.96, 0.97, and 0.96 for the skin, hair, and eye pigmentation scans, respectively.

“The Pearson correlation coefficients between the linear model t-statistics from the two GWAS results are 0.96, 0.97, and 0.96 for the skin, hair, and eye pigmentation scans, respectively.”

Classified as probably not a substantial claim.

The inner upper arm was chosen as a site of sampling to avoid as much as possible confounding by variable sun exposure and variability in tanning ability.

“The inner upper arm was chosen as a site of sampling to avoid as much as possible confounding by variable sun exposure and variability in tanning ability.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Global-level variation in skin color is likely driven primarily by natural (ecological) selection in response to UV radiation levels.

“For skin color, global-level variation is likely driven primarily by natural (ecological) selection in response to UV radiation levels.”

• cites [2]–[5]Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

There were 186 SNPs that had a p-value <0.01 in two or more populations, none of which were part of the replication set.

“There were 186 SNPs that had a p-value <0.01 in two or more populations, none of which were part of the replication set.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Two SNPs on chromosome X with heterozygous genotypes in males were excluded.

“Two SNPs on chromosome X with heterozygous genotypes in males were also excluded.”

Classified as probably not a substantial claim.

Based on quality control criteria, genotypes were obtained for 21, 26, and 34 of the SNPs selected from the results of the skin, hair, and eye pigmentation GWAS respectively.

“genotypes were obtained for 21, 26, and 34 of the SNPs selected from the results of the skin, hair, and eye pigmentation GWAS respectively”

Classified as probably not a substantial claim. May combine two claims.

There is no obvious ecological selective pressure to explain the variation of hair and eye color or local variation in skin pigmentation.

“Unlike for global skin pigmentation, there is no obvious ecological selective pressure to explain the variation of hair and eye color or local variation in skin pigmentation.”

Probably not a substantial claim: may not pass S3 (load-bearing).

SNPs with a minor allele frequency <1% or >10% missing rate were excluded from the analysis.

“SNPs with a minor allele frequency (maf) <1% or >10% missing rate were excluded from the analysis.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Skin pigmentation forms a gradient correlated with latitude, and variation in hair and eye color is particularly extensive in Europe.

“Skin pigmentation forms a gradient correlated with latitude, and variation in hair and eye color is particularly extensive in Europe (reviewed in [1]).”

• cites [1] Parra EJ (2007) Human pigmentation variation: evolution, genetic basis, and implications for public health. American journal of physical anthropology Suppl 45: 85–105. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Age was not correlated with any of the pigmentation traits, most likely due to the narrow age range in the study.

“Age was not correlated with any of the pigmentation traits most likely due to the narrow age range in our study”

May combine two claims.

The derived allele (G) at rs12913832 is recessive and is associated with blue eye color.

“The derived allele (G) at rs12913832 is recessive and is associated with blue eye color.”

• cites [33] H Eiberg, 2008, Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression, Human genetics sourceNot checked yet

  Not checked in the free run.

• cites [34] RA Sturm, 2008, A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color, American journal of human genetics sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

The four countries (Ireland, Poland, Italy, Portugal), located near the geographical extremes of Europe, capture a large fraction of European phenotypic variation.

“These countries, located near the geographical extremes of Europe, were chosen to capture a large fraction of European phenotypic variation.”

May combine two claims.

The existing signal at rs1667394 was abolished (p = 0.73) after adjusting for the recessive effect of rs12913832, indicating that rs1667394 and rs12913832 likely represent the same association signal.

“Furthermore the existing signal at rs1667394 was abolished (p = 0.73), indicating that rs1667394 and rs12913832 likely represent the same association signal.”

Classified as probably not a substantial claim. May combine two claims.

Liu et al. report that quantitation improved the power to detect association signals at some known pigmentation genes and facilitated the identification of two novel replicated eye color loci at 17q25 and 21q22.

“These authors report that the quantitation improved the power to detect the association signals at some known pigmentation genes and also facilitated the identification of two novel replicated eye color loci at 17q25 and 21q22.”

• cites [11] F Liu, 2010, Digital quantification of human eye color highlights genetic association of three new loci, PLoS genetics sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The Bonferroni correction was applied and the genome-wide 5% significance threshold was considered to be a p-value <1.6×10−7 (0.05/313,763).

“To account for multiple testing, the Bonferroni correction was applied and the genome-wide 5% significance threshold was considered to be a p-value <1.6×10−7 (0.05/313,763).”

May combine two claims.

rs12913832 is a strong predictor of eye color; it alone explains 44-48% of the variance in quantitative measures of eye color in Dutch Europeans.

“rs12913832 is a strong predictor of eye color; it alone explains 44–48% of the variance in quantitative measures of eye color in Dutch Europeans [11].”

• cites [11] F Liu, 2010, Digital quantification of human eye color highlights genetic association of three new loci, PLoS genetics sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Twenty-one, 26, and 34 of the candidate SNPs passed the genotyping quality control for the skin, hair, and eye pigmentation replication, respectively, and these include the top association signals of the three GWAS.

“Twenty-one, 26, and 34 of the candidate SNPs passed the genotyping quality control for the skin, hair, and eye pigmentation replication, respectively, and these include the top association signals of the three GWAS.”

May combine two claims.

rs1667394 is located in an intron of HERC2 near the OCA2 gene, the major locus determining eye color, and has been reproducibly associated with eye color.

“rs1667394 is located in an intron of HERC2 near the OCA2 gene, the major locus determining eye color and this SNP has been reproducibly associated with eye color [13].”

• cites [13] P Sulem, 2007, Genetic determinants of hair, eye and skin pigmentation in Europeans, Nature genetics sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

To avoid confounding by population structure at the replication stage, only 294 individuals (153 males and 141 females) who reported that all four grandparents had ancestry in the countries of sampling were considered.

“To avoid confounding by population structure at the replication stage, we only considered 294 individuals (153 males and 141 females), who reported that all of their four grandparents had ancestry in the countries of sampling.”

May combine two claims.

Considering the number of loci for the Bonferroni correction (18, 24, and 26 for skin, hair and eye pigmentation) instead of the number of SNPs leads to a less conservative correction but to identical conclusions.

“Considering the number of loci for the Bonferroni correction (18, 24, and 26 for skin, hair and eye pigmentation) instead of the number of SNPs leads to a less conservative correction but to identical conclusions.”

May combine two claims.

Not accounting for European population structure, particularly when phenotypes are stratified along axes of genetic differentiation, leads to highly significant false positive results (LCT locus for skin pigmentation) or inflated true positive results (OCA2/HERC2 locus for eye pigmentation).

“These results demonstrate that not accounting for European population structure, particularly in this situation where the phenotypes are stratified along axes of genetic differentiation, leads to highly significant false positive results (LCT locus for skin pigmentation) or inflated true positive results (OCA2/HERC2 locus for eye pigmentation) (Figure S2).”

May combine two claims.

The use of categories necessarily results in a loss of information, leading to a loss of statistical power to detect genetic effects.

“The use of categories necessarily results in a loss of information, leading to a loss of statistical power to detect genetic effects.”

May combine two claims.

Since the GWAS included only females, an analysis considering only females obtained qualitatively identical conclusions: no SNP is reproducibly associated with skin or hair pigmentation, while five SNPs at the OCA2/HERC2 locus are reproducibly associated with eye pigmentation in the replication female-only cohort.

“Since the GWAS included only females, we also performed the analysis considering only the females and obtained qualitatively identical conclusions: no SNP is reproducibly associated with skin or hair pigmentation, while five SNPs at the OCA2/HERC2 locus are reproducibly associated with eye pigmentation in the replication female only cohort.”

May combine two claims.

rs1667394 is also in LD with rs12913832 (D' = 1, r2 = 0.65), which was not genotyped in the study but is thought to be the likely causative variant for blue versus brown eye color by genetic and functional analyses.

“rs1667394 is also in LD with rs12913832 (D’ = 1, r2 = 0.65), which was not genotyped in our study but is thought to be the likely causative variant for blue versus brown eye color by genetic and functional analyses [33], [34].”

• cites [33] H Eiberg, 2008, Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression, Human genetics sourceNot checked yet

  Not checked in the free run.

• cites [34] RA Sturm, 2008, A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color, American journal of human genetics sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Skin, hair, and eye color are all quantitative traits, and their true distributions are only approximated by categories.

“Skin, hair, and eye color are in fact all three quantitative traits, and their true distributions are only approximated by categories.”

May combine two claims.

Objective and quantitative phenotyping has the potential to improve the power to detect a genetic effect compared to GWAS based on subjective categorical phenotypes, but due to small sample size the study was only sufficiently powered to identify the major genetic effect of the HERC2/OCA2 locus on eye color.

“Objective and quantitative phenotyping has the potential to improve the power to detect a genetic effect compared to GWAS based on subjective categorical phenotypes, but due to small sample size our study was only sufficiently powered to identify the major genetic effect of the HERC2/OCA2 locus on eye color.”

• AssumptionThe authors state this as an assumption: The small sample size explains why the GWAS p-values for other causative loci are not clearly smaller than those expected by chance.

May combine two claims.

The fact that the study did not detect reproducible associations with skin or hair color suggests that, unlike eye color, skin and hair pigmentation variation in Europe are not determined by major loci.

“The fact that we did not detect reproducible associations with skin or hair color suggests that, unlike eye color, skin and hair pigmentation variation in Europe are not determined by major loci.”

• AssumptionThe authors state this as an assumption: The small sample size explains why the GWAS p-values for other causative loci are not clearly smaller than those expected by chance.

May combine two claims.

Other eye color loci reported have been estimated each to explain less than 1% of the phenotypic variation, for which the GWAS sample size is under-powered.

“In contrast, other eye color loci reported [11] have been estimated each to explain less than 1% of the phenotypic variation, for which our GWAS sample size is under-powered.”

• cites [11] F Liu, 2010, Digital quantification of human eye color highlights genetic association of three new loci, PLoS genetics sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

One potential reason for the conflicting results is the different instruments used: in early studies using EEL and Photovolt broad-spectrum spectrophotometers, skin pigmentation estimates may be confounded by hemoglobin level to a greater extent than for the DermaSpectrometer used in the present study.

“One potential reason for the conflicting results is the different instruments used. In early studies, which used the Evans Electric Limited (EEL) and Photovolt broad-spectrum spectrophotometers, skin pigmentation estimates may be confounded by the hemoglobin level to a greater extent than for the DermaSpectrometer used in the present study [46].”

• cites [46] H Takiwaki, 1998, Measurement of skin color: practical application and theoretical considerations, J Med InvestNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

rs16891982 in SLC45A2 (98% frequency in CEU for the derived allele) may contribute to skin pigmentation differences in Europe as suggested in a candidate gene study for subjective skin color.

“This variant (98% frequency in CEU for the derived allele) may contribute to skin pigmentation differences in Europe as suggested in a candidate gene study for subjective skin color [39].”

• cites [39] J Graf, 2005, Single nucleotide polymorphisms in the MATP gene are associated with normal human pigmentation variation, Human mutation sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Differences in skin pigmentation between sexes are likely population specific: whereas DermaSpectrometer M index measurements in this study show European males to have lighter skin pigmentation than European females, measurements in Island Melanesian, African Caribbeans, and African Americans have shown that in these populations males have darker skin pigmentation than females.

“Lastly, we emphasize that differences in skin pigmentation between sexes are likely population specific. Whereas DermaSpectrometer M index measurements in this study show European males to have lighter skin pigmentation than European females, DermaSpectrometer M index measurements of skin pigmentation in Island Melanesian, African Caribbeans, and African Americans have shown that in these populat”

• cites [6] HL Norton, 2006, Skin and hair pigmentation variation in Island Melanesia, Am J Phys Anthropol sourceNot checked yet

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• cites [38] MD Shriver, 2003, Skin pigmentation, biogeographical ancestry and admixture mapping, Human genetics sourceNot checked yet

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• cites [47] C Bonilla, 2005, The 8818G allele of the agouti signaling protein (ASIP) gene is ancestral and is associated with darker skin color in African Americans, Hum Genet sourceNot checked yet

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May combine two claims.

In candidate gene studies, R163Q has shown either no association, or association of the minor, derived allele (Q variant) with lighter skin pigmentation.

“In candidate gene studies, R163Q has shown either no association, or association of the minor, derived allele (Q variant) with lighter skin pigmentation [41]–[45].”

• cites [41]–[45]Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The same trend in M index was reported previously in a sample of European Americans.

“The same trend in M index was reported previously in a sample of European Americans [38].”

• cites [38] MD Shriver, 2003, Skin pigmentation, biogeographical ancestry and admixture mapping, Human genetics sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Not correcting for ancestry leads to an overestimation of the effect of pigmentation genes, like the HERC2/OCA2 locus for eye color, or results in a false positive association of loci that have differentiated along the same geographical axes, e.g. the strong association of variation at the lactase gene (LCT) with skin color that the study observed.

“Not correcting for ancestry leads to an overestimation of the effect of the pigmentation genes, like the HERC2/OCA2 locus for eye color, or results in a false positive association of loci that have differentiated along the same geographical axes, e.g. the strong association of variation at the lactase gene (LCT) with skin color that we observed.”

May combine two claims.

This genetic factor explains 10.7% of the blond to black variation in hair color in populations of European ancestry, requiring a sample size of 327 to achieve 80% power.

“This genetic factor explains 10.7% of the blond to black variation in hair color in populations of European ancestry, requiring a sample size of 327 to achieve 80% power.”

• cites [9] J Han, 2008, A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation, PLoS genetics sourceNot checked yet

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May combine two claims.

In Europe, variation at rs1426654 in SLC24A5 does not contribute to skin pigmentation differences since the derived allele associated with light skin pigmentation has been swept to fixation (100% frequency in HapMap CEU).

“In Europe, variation at rs1426654 in SLC24A5 does not contribute to skin pigmentation differences since the derived allele associated with light skin pigmentation has been swept to fixation (100% frequency in HapMap CEU).”

Probably not a substantial claim: may not pass S3 (load-bearing).

In candidate gene association studies, these three variants have been shown to contribute to quantified skin pigmentation variation in admixed European/African populations.

“In candidate gene association studies, these three variants have been shown to contribute to quantified skin pigmentation variation in admixed European/African populations [4], [36]–[38].”

• cites [4] HL Norton, 2007, Genetic evidence for the convergent evolution of light skin in Europeans and East Asians, Molecular biology and evolution sourceNot checked yet

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• cites [36]–[38]Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

MC1R is an extensively studied human pigmentation gene whose variants have been associated with red hair, fair skin, sun sensitivity, and freckling in populations of European ancestry.

“MC1R is an extensively studied human pigmentation gene whose variants have been associated with red hair, fair skin, sun sensitivity, and freckling in populations of European ancestry (see [40] for a review).”

• cites [40] C Dessinioti, 2011, Melanocortin 1 receptor variants: functional role and pigmentary associations, Photochemistry and photobiology sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The Stokowski et al. GWAS showed that non-synonymous variants in three genes, rs1426654 SLC24A5, rs16891982 SLC45A2, and rs1042602 TYR, contribute to differences in spectroscopic skin pigmentation measurements in South Asians.

“However our results can be compared to the Stokowski et al. [17] GWAS, which showed that non-synonymous variants in three genes, rs1426654 SLC24A5, rs16891982 SLC45A2, and rs1042602 TYR, contribute to differences in spectroscopic skin pigmentation measurements in South Asians.”

• cites [17] RP Stokowski, 2007, A genomewide association study of skin pigmentation in a South Asian population, American journal of human genetics sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable).

One should be careful about generalizing the finding that country-based correction performs equivalently to PC-based correction to other more heterogeneous samples like larger pan-European and European-American samples.

“One should be careful about generalizing this finding to other more heterogeneous sample like larger pan-European and European-American samples.”