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Cited by 317melanin and skin pigmentationGenetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and Animals

A Genomewide Association Study of Skin Pigmentation in a South Asian Population

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Stokowski, Renee P., Pant, P.V. Krishna, Dadd, Tony, Fereday, Amelia, Hinds, David A., Jarman, Carl, Filsell, Wendy, Ginger, Rebecca S. +3 more·2007·The American Journal of Human Genetics
DOI 10.1086/522235PMC PMC2276347
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Abstract

We have conducted a multistage genomewide association study, using 1,620,742 single-nucleotide polymorphisms to systematically investigate the genetic factors influencing intrinsic skin pigmentation in a population of South Asian descent. Polymorphisms in three genes--SLC24A5, TYR, and SLC45A2--yielded highly significant replicated associations with skin-reflectance measurements, an indirect measure of melanin content in the skin. The associations detected in these three genes, in an additive manner, collectively account for a large fraction of the natural variation of skin pigmentation in a South Asian population. Our study is the first to interrogate polymorphisms across the genome, to find genetic determinants of the natural variation of skin pigmentation within a human population.

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Written from the paper’s full text.

TL;DR

This multistage genomewide association study measured 1,620,742 SNPs and identified replicated associations between skin reflectance and polymorphisms in SLC24A5, TYR, and SLC45A2 in a South Asian population. The three associated nonsynonymous SNPs act additively and collectively account for a large fraction of natural skin-pigmentation variation.

Key findings

  • In cohort 1, 42 SNPs reached genomewide significance (Bonferroni threshold P = 3.3 × 10⁻⁸); 39 of 42 were in a single 2.4-Mb region of 15q21.1-21.2. The strongest SNP, rs1834640, had P = 1.0 × 10⁻⁵⁰ and a 45% allele-frequency difference between high- and low-reflectance groups, located 21 kb from SLC24A5.
  • In the independent replication cohort 2, 32 (76%) of 42 SNPs had P < .05. rs1834640 replicated with P = 3.28 × 10⁻¹⁵ and a 36% allele-frequency difference. Dense genotyping of 408 SNPs in the chromosome 15 region identified rs1426654 (SLC24A5 p.A111T) as most significant (P = 1.06 × 10⁻¹⁸; 39% allele-frequency difference; R² = 0.93 with rs1834640), and conditional analysis supported a single primary association.
  • Three nonsynonymous SNPs showed genomewide significance: rs1426654 in SLC24A5, rs16891982 in SLC45A2, and rs1042602 in TYR. Their squared correlations with the dichotomous skin-reflectance trait were R² = 0.33, 0.036, and 0.025, respectively. No significant dominance effects (P = .58, .20, .91) or pairwise interactions (P = .77, .38, .12) were found, consistent with an additive model.
  • Candidate-gene results included OCA2 rs1037208 (joint cohort P = 5.6 × 10⁻⁵) and MC1R rs2228479 (P = 6.8 × 10⁻⁴); ASIP rs6058017 showed no allele-frequency difference between reflectance groups (|Dp| = 0.008), and individual genotyping of it was unsuccessful.

Methods

  • South Asian volunteers were recruited at 150 UK sites; inclusion required parents or all four grandparents born in India, Pakistan, Bangladesh, or Sri Lanka. Skin pigmentation was measured by reflectance spectroscopy (Minolta chromameter L* value); low-reflectance (L) was maxL* ≤56 and high-reflectance (H) was maxL* ≥63. Cohort 1 recruited 395 L and 383 H individuals; cohort 2 recruited 119 L and 116 H individuals.
  • Pooled genotyping estimated allele-frequency differences for 1,620,742 SNPs using DNA pools from 286 L and 285 H cohort 1 individuals. The top 30,000 SNPs were individually genotyped in 737 cohort 1 individuals (363 L, 374 H) after quality control; 42 genomewide-significant SNPs were then genotyped in cohort 2, and 408 SNPs were genotyped across the chromosome 15 region.
  • Association tests used logistic regression with sex and the first five principal components from 292 genomic-control SNPs as covariates, with likelihood-ratio tests. The genomewide Bonferroni threshold was 0.05/1,502,205 = 3.3 × 10⁻⁸. Conditional, dominance, and pairwise-interaction models were also tested.

Limitations

  • Stated by the authors: the strict Bonferroni correction across 1,502,205 tests combined with the pooled genotyping design greatly reduces power to detect real SNP associations with small effects, so loci other than TYR, SLC45A2, and SLC24A5 may affect skin-pigmentation variation in South Asians.
  • Stated by the authors: because the study used the tails of the skin-reflectance distribution, it cannot directly determine the overall fraction of trait variance in the population accounted for by the associated SNPs; the authors also note they cannot completely exclude multiple independent associations in the chromosome 15 region.
  • Evident from the text: the sample is a UK South Asian population, and the authors note that the three implicated SNPs are essentially monomorphic in African and East Asian populations, so their contribution to pigmentation variation in other global populations is likely to differ. The ASIP SNP could not be individually genotyped, and the mixed-sex pooled design would not have power to detect a female-specific association.

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Integrity signals

Registry

Crossref · 10.1086/522235

Cites

57 of 57 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 37 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Polymorphisms in SLC24A5, TYR, and SLC45A2 yielded highly significant replicated associations with skin-reflectance measurements in a South Asian population.

    “Polymorphisms in three genes-SLC24A5, TYR, and SLC45A2-yielded highly significant replicated associations with skin-reflectance measurements, an indirect measure of melanin content in the skin.”
    Quote in the paperSubstantial claim
  • Findingown data

    After adjustment for the first five principal components and sex, the remaining 291 polymorphic GC SNPs did not reveal a significant inflation in single-SNP test statistics for association with skin reflectance (mean deviance 1.0232; P = .37).

    “The results for the remaining 291 SNPs did not reveal a significant inflation in single-SNP test statistics for association with skin reflectance (mean deviance 1.0232; ).Thus, no fur-P p .37 ther corrections for population structure were deemed necessary in association tests for other SNPs in cohort 1 or cohort 2.”
    Quote in the paperSubstantial claim
  • Findingown data

    The inferred cluster-membership values for a two-cluster model correlate with reported geographical ancestry.

    “The inferred cluster-membership values for a two-cluster model correlate with reported geographical ancestry.”
    Quote in the paperSubstantial claim
  • Findingown data

    In cohort 2, 32 (76%) of the 42 genomewide-significant SNPs from cohort 1 yielded P values below .05.

    “A majority of the associated SNPs, 32 (76%) of 42, yielded P values with a significance threshold of !.05 (table 5).”
    Quote in the paperSubstantial claim
  • Findingown data

    Four of the top five principal components show significant association with reported ancestry regions in an analysis of variance.

    “In addition, four of the top five principal components show significant association with reported ancestry regions in an analysis of variance”
    Quote in the paperSubstantial claim
  • May combine two claims. 35
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Findingown data

    A conservative Bonferroni threshold for significance of association (α = 0.05/1,502,205 = 3.3 × 10^-8) was employed, and 42 SNPs were associated at this level of significance across the genome.

    “Therefore, we employed a conservative Bonferroni threshold for significance of association, , and found 42 SNPs as-Ϫ8 a p 0.05/1,502,205 p 3.3 # 10 sociated at this level of significance across the genome (table 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the dense SNP set within 15q21.1-21.2, 408 SNPs were successfully assayed and revealed several other significant associations across the region.

    “A total of 408 SNPs were successfully assayed, and association test results for this set of SNPs revealed several other significant associations across the region (table 6 and fig.3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The strongest SNP association for the entire genome is in this region, with an allele-frequency difference of 45% between the H and L reflectance groups, yielding a P value of 1.0 × 10^-50.

    “The strongest SNP association for the entire genome is in this region, with an allele-frequency difference of 45% between the H and L reflectance groups, yielding a P value of 1.0#10 Ϫ50 .”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The first and fifth principal components showed significant associations with skin reflectance (classified as L or H) in logistic regression with sex as a covariate (P = 4.6 × 10^-22 and P = 1.7 × 10^-3, respectively).

    “The first and fifth components showed significant associations ( and , Ϫ22 Ϫ3 P p 4.6 # 10 P p 1.7 # 10 respectively).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The most significant association in the chromosome 15 region was for rs1426654, a nonsynonymous polymorphism (p.A111T) in SLC24A5, with P=1.06×10−18 and a 39% allele-frequency difference between high- and low-reflectance groups.

    “The most significant association in this region was observed for rs1426654, a nonsynonymous polymorphism (p.A111T) in SLC24A5, with P p and a 39% allele-frequency difference be-Ϫ18 1.06 # 10 tween the high-and low-reflectance groups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The primary associated SNP rs1426654 in SLC24A5 has the largest effect on skin reflectance of the three SNPs, with R^2=0.33, compared with R^2=0.036 for rs16891982 in SLC45A2 and R^2=0.025 for rs1042602 in TYR.

    “The primary associated SNP, rs1426654 in SLC24A5, has the largest effect on skin reflectance of the three SNPs, with , compared with 2 R p 0.33 for rs16891982 in SLC45A2 and for 2 2 R p 0.036 R p 0.025 rs1042602 in TYR.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Matching the two phenotypic pools by inferred ancestry reduced population stratification considerably, as measured by a reduction in the sum of χ2 statistics versus unmatched groups, though residual stratification remained statistically significant (P = 3.9 × 10^-5).

    “This matching required us to exclude ∼25% of the original individuals but reduced the population stratification considerably, as can be measured by a reduction in the sum of x 2 statistics versus the unmatched groups (table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The largest three eigenvalues for the true data set were larger than the largest eigenvalue in any of the permuted data sets (P < .01); the largest five eigenvalues in the true data set were observed in fewer than half the permuted data sets.

    “The largest three eigenvalues for the true data set were larger than the largest eigenvalue in any of the permuted data sets ( ); the largest five eigen-P !.01values in the true data set were observed in fewer than half the permuted data sets.”
    Quote in the paperSubstantial claim

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

    Findingnone given

    This SNP, rs1834640, is located 21 kb from the closest gene, SLC24A5.

    “This SNP, rs1834640, is located 21 kb from the closest gene, SLC24A5.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    After application of quality filters to genotypes and DNA samples, a total of 25,928 SNPs for 737 individuals (363 L and 374 H) were used for the association analysis, including 292 polymorphic GC SNPs.

    “After application of quality filters to the genotypes and the DNA samples, a total of 25,928 SNPs for 737 individuals, 363 L and 374 H, were used for the association analysis, including 292 polymorphic GC SNPs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The last associated SNP, rs16891982, is a nonsynonymous polymorphism (p.L374F) in the gene SLC45A2 on chromosome 5.

    “The last associated SNP, rs16891982, is also a nonsynonymous polymorphism (p.L374F) in the gene SLC45A2 on chromosome 5.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The replicated SNPs included nonsynonymous polymorphisms in TYR and SLC45A2 and 30 SNPs in the 2.4-Mb region on chromosome 15.

    “These included the nonsynonymous polymorphisms in TYR and SLC45A2, as well as 30 SNPs in the 2.4-Mb region on chromosome 15.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The results yielded good evidence of more than one distinct genetic population cluster in the set of 778 individuals but yielded little support for more than two population clusters.

    “The results yielded good evidence of more than one distinct genetic population cluster in our set of 778 individuals but yielded little support for more than two population clusters.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of the 407 SNPs genotyped in the region, only rs1834640 is in high linkage disequilibrium with rs1426654 (R^2>0.9), and 3 more SNPs are in moderate linkage disequilibrium (R^2>0.5).

    “Of the 407 SNPs genotyped in this region, only rs1834640 is in high linkage disequilibrium with rs1426654 ( ), and 3 2 R 1 0.9 more SNPs are in moderate linkage disequilibrium ( 2 R 1 ) (fig.3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In cohort 2, the most significant association among the 42 SNPs was for rs1834640 on 15q21.1, with P=3.28×10−15 and a 36% allele-frequency difference between high- and low-reflectance groups.

    “As was seen in cohort 1, the most significant association among these SNPs in cohort 2 was for rs1834640 on 15q21.1, with and a Ϫ15 P p 3.28 # 10 36% allele-frequency difference between the high-and low-reflectance groups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Individuals of southern (mainly Sri Lankan) and eastern (mainly Bangladeshi) origin have a similar distribution of admixture, which is distinct from individuals of northwestern (mainly Punjabi) origin.

    “Individuals of southern (mainly Sri Lankan) and eastern (mainly Bangladeshi) origin have a similar distribution of admixture, which is distinct from individuals of northwestern (mainly Punjabi) origin (fig.2).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Under the null (one-cluster) model of no population structure, there was a large excess of small P values in χ2 tests for association with skin color, and a global test for population stratification based on the sum of χ2 statistics was highly statistically significant (P < 10^-40).

    “Under the null (one-cluster) model of no population structure, for which the L and H groups are assumed to be well matched, we observed a large excess of small P values in x 2 tests for association with skin color (table 2), and a global test for population stratification based on the sum of x 2 statistics 46 was highly statistically significant”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • May combine two claims.

    Findingown data

    Likelihood-ratio tests showed no significant deviations from multiplicative risk for dominance for rs1426654 (P=.58), rs16891982 (P=.20), or rs1042602 (P=.91).

    “Likelihood-ratio tests were used to assess the significance of an added dominance term, but none of the tests showed significant deviations from multiplicative risk ( for rs1426654, P p .58 for rs16891982, and for rs1042602), which P p .20 P p .91 provides no evidence to support dominant or recessive inheritance for any of the three SNPs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Within each of these genes, polymorphisms met genomewide significance on association tests, with associations replicated in a second South Asian cohort.

    “Within each of these genes, we found polymorphisms that met genomewide significance on association tests, with the associations replicated in a second South Asian cohort.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both rs12910433 and rs2228479 were individually genotyped in cohort 1; rs12910433 showed no evidence of association (P=.3), while rs2228479 had the lowest P value (P=6.8×10−4) of several MC1R SNPs individually genotyped.

    “Both these SNPs were individually genotyped in cohort 1 in our study, and, whereas the OCA2 SNP rs12910433 showed no evidence of association ( ), P p .3 the MC1R SNP rs2228479 had the lowest P value (P p ) of several MC1R SNPs that were individually Ϫ4 6.8 # 10 genotyped.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    rs6058017 was included in the pooled study but showed no allele-frequency difference between low- and high-reflectance groups (0.008), and attempts to individually genotype this SNP in cohort 1 were unsuccessful.

    “This SNP was included in our P !.001pooled study but showed no allele-frequency difference between the low-and high-reflectance groups ( ˆ FDpF p ), and attempts to individually genotype this SNP in 0.008 cohort 1 were unsuccessful.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    rs26722 was assayed in the present study but showed weaker evidence of association with skin-reflectance measurements in the South Asian population (joint cohort association P=.02) compared with the significantly associated rs16891982 SNP.

    “Whereas the promoter variants in SLC45A2 were not included in our study, rs26722 was assayed in the present study but showed weaker evidence of association with skin-reflectance measurements in our South Asian population (joint cohort association ), as compared with the significantly associated P p .02 rs16891982 SNP.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Until very recently, few direct studies to identify genes responsible for the normal range of human skin pigmentation have been reported, and all these studies investigated only known pigmentation-disorder genes in normal skin-color variation.

    “However, until very recently, few direct studies to identify the genes responsible for the normal range of human skin pigmentation have been reported 13,[17][18][19][20][21][22][23][24][25][26] ; in addition, all these studies have investigated the role of only known pigmentation-disorder genes in normal skin-color variation.”
    Quote in the paperSubstantial claim0 of 3 sources checked
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    • cites [17] source

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    Premisecitation

    Skin pigmentation is a polygenic quantitative trait with high heritability in humans.

    “Epidemiological studies in humans show that skin pigmentation is a polygenic quantitative trait with high heritability, [8][9][10]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] source

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  • Classified as probably not a substantial claim.

    Study design and conductown data

    Population structure was modeled jointly for both population cohorts using PCA of standardized genotypes on the 292 polymorphic GC SNPs that passed quality filters.

    “Population structure was modeled jointly for both population cohorts used in this study, with use of a PCA of the standardized genotypes on the 292 polymorphic GC SNPs that passed our quality filters.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Human skin color is largely determined by two biological components, melanin and hemoglobin, and one major environmental component, exposure to UV light.

    “Human skin color is largely determined by two biological components, melanin and hemoglobin, and one major environmental component, exposure to UV light.42”
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  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Sex was included as a covariate in logistic regression because it was not explicitly matched for in selecting study participants.

    “Sex is a known confounder with skin pigmentation 24 that was not explicitly matched for in selecting study participants; thus, it was also included as a covariate in logistic regression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The South Asian population has a wide natural variation in skin pigmentation and is the most genetically diverse population outside of Africa, making it well suited for investigating the complex genetic trait of human skin pigmentation.

    “The population of South Asia, which, in this study, includes India, Pakistan, Bangladesh, and Sri Lanka, has a wide natural variation in skin pigmentation and consists of the most genetically diverse population outside of Africa, 41 which makes it well suited for the investigation of the complex genetic trait of human skin pigmentation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] source

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  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Single-SNP tests for association with skin reflectance were performed with logistic regression, including sex and five principal components of the GC SNP genotypes as covariates.

    “Single-SNP tests for association with skin reflectance were performed with logistic regression, including sex and five principal components of the GC SNP genotypes as covariates.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The highest L* value (maxL*) from hairless, sun-protected sites on the arm was used to define intrinsic skin reflectance, thereby controlling for confounding effects due to sun exposure and hair.

    “Therefore, the highest L* value (maxL*) from hairless, sun-protected sites on the arm was used to define intrinsic skin reflectance in this study, thereby controlling for confounding effects due to sun exposure and hair.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Inclusion of all individuals in individual genotyping maximizes power to detect associations because population structure can be explicitly modeled, unlike in pooled genotyping.

    “These included individuals who had been excluded from the balanced pools constructed for cohort 1; for, unlike pooled genotyping, with individual genotypes we can explicitly model population structure in the association analysis, and, therefore, the inclusion of all individuals maximizes our power to detect associations.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Association tests were performed with logistic regression, with covariates to account for sex and population structure, with likelihood-ratio tests to assess significance of association with SNP genotypes.

    “Association tests were performed with logistic regression, with covariates to account for sex and population structure, with the use of likelihood-ratio tests to assess the significance of association with SNP genotypes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Although other associations of small effect within the chromosomal region cannot be ruled out, the evidence points strongly to a single association of large effect size located at or in strong disequilibrium with rs1426654 within SLC24A5.

    “Although we cannot rule out other associa-0.5tions of small effect within this chromosomal region, the evidence points strongly to a single association of large effect size, located at or in strong disequilibrium with the nonsynonymous SNP rs1426654 within SLC24A5.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The data are consistent with a single strong primary association at rs1426654 in SLC24A5, and the multiplicity of apparent single-SNP associations in the region can be explained by linkage disequilibrium with this SNP.

    “Thus, the data are consistent with the existence of a single strong primary association at rs1426654 in the SLC24A5 gene, and the multiplicity of apparent single-SNP associations in this region can be explained by the pattern of linkage disequilibrium with this SNP (fig.3).”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    We tested for residual systematic inflation in the test statistics by applying this likelihood-ratio test to all samples taken together (cohorts 1 and 2) for the GC SNPs that were polymorphic and passed quality filters.

    “We tested for residual systematic inflation in the test statistics by applying this likelihood-ratio test to all samples taken together (cohorts 1 and 2) for the GC SNPs that were polymorphic in the study population and that passed our quality filters for individual genotyping.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The contributions of these polymorphisms to skin pigmentation were independent and additive across genes, with no evidence of dominant or recessive effects at any of these loci.

    “The contributions of these polymorphisms to skin pigmentation were found to be independent and additive across genes, with no evidence of dominant or recessive effects at any of these loci.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Two functional promoter variants and another nonsynonymous polymorphism in SLC45A2, rs26722 (p.E272K), have also been significantly associated with subjectively measured skin color in a population of European ancestry.

    “For example, two functional promoter variants and another nonsynonymous polymorphism in SLC45A2, rs26722 (p.E272K), have also been significantly associated with subjectively measured skin color in a population of European ancestry.20”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    At the time of the study, mutations in TYR and SLC45A2 were known to be involved in OCA1 and OCA4, but their contribution to the normal range of skin pigmentation between and within populations was just beginning to be studied.

    “At the time of this study, mutations in two of these genes, TYR and SLC45A2, were known to be involved in different forms of oculocutaneous albinism (OCA1 [MIM 203100] and OCA4 [MIM 606574]), 49,50 yet their contribution to the normal range of skin pigmentation between and within populations was just beginning to be studied.”
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    Premisenone given

    SLC24A5 was an unknown pigmentation gene during the study.

    “The remaining locus, SLC24A5, which displays the largest genetic effect on pigmentation status in the South Asian population studied here, was an unknown pigmentation gene during our study.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Several studies comparing allele frequencies of candidate skin-pigmentation SNPs across multiple global populations present evidence supporting an independent genetic mechanism for the lighter skin pigmentation of East Asians that is distinct from genetic factors influencing lighter pigmentation in Europeans.

    “Furthermore, as was mentioned earlier in this discussion, several studies comparing allele frequencies of candidate skin-pigmentation SNPs across multiple global populations present evidence supporting an independent genetic mechanism for the lighter skin pigmentation of East Asians that is distinct from genetic factors influencing lighter pigmentation in Europeans.12,13,25”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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  • May combine two claims.

    Premisecitation

    All three SNPs are essentially monomorphic in African and East Asian populations and thus are unlikely to contribute significantly to skin-pigmentation variation within those groups.

    “All three of the SNPs are essentially monomorphic in African and East Asian populations and thus are unlikely to contribute significantly to skin-pigmentation variation within those groups.13,25,29,30”
    Quote in the paperSubstantial claim0 of 3 sources checked
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  • May combine two claims.

    Premisecitation

    The TYR SNP rs1042602 is highly polymorphic in all European populations, but previous studies found that this SNP was not significantly associated with skin-reflectance measurements in a white population.

    “In comparison, the TYR SNP rs1042602 is highly polymorphic in all European populations, but, despite its variability, previous studies found that this SNP was not significantly associated with skin-reflectance measurements in a white population.13,21,24,29”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The SLC45A2 SNP rs16891982 displays a gradient of increasing minor-allele frequency in European populations from north to south and has been significantly associated with subjectively measured skin color in a population of European ancestry.

    “In contrast to the TYR SNP, the SLC45A2 SNP rs16891982 displays a gradient of increasing minor-allele frequency in European populations from north to south 13,26,52 and has been significantly associated with subjectively measured skin color in a population of European ancestry.19”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    SLC24A5 has since been shown to play an important role in pigmentation because a mutation in this gene was identified as the genetic basis of the hypopigmentation phenotype in golden zebrafish.

    “The SLC24A5 gene has since been shown to play an important role in pigmentation, because a mutation in this gene was identified as the genetic basis of the hypopigmentation phenotype in golden zebrafish.22”
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Another study found an association with skin reflectance in a Tibetan population under an epistatic model (P=.01) for a pair of SNPs in OCA2 and MC1R-rs12910433 and rs2228479 (p.V92M).

    “Another study found an association with skin reflectance in a Tibetan population under an epistatic model ( ) for a pair P p .01 of SNPs in OCA2 and MC1R 17 -rs12910433 and a nonsynonymous polymorphism, rs2228479 (p.V92M), respectively.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] source

      Not checked in the free run.

45 of 45

  • The paper relies on this without support.

    This study is the first to interrogate polymorphisms across the genome to find genetic determinants of natural variation of skin pigmentation within a human population.

    “Our study is the first to interrogate polymorphisms across the genome, to find genetic determinants of the natural variation of skin pigmentation within a human population.”

  • The paper relies on this without support.

    The 98 randomly selected individuals used to estimate the maxL* distribution are representative of the South Asian population in the United Kingdom.

    “Skin chromameter measurements for 98 randomly selected individuals of South Asian ancestry living in the United Kingdom were used to estimate the distribution of maxL* within the South Asian population (fig.1).”

  • The paper relies on this without support.

    The South Asian population is highly genetically diverse and ancestry is highly confounded with skin pigmentation.

    “This population is known to be highly genetically diverse, and, because ancestry is known to be highly confounded with skin pigmentation, the treatment of population structure was crucial to our association analysis.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • SLC24A5 is called SLC24A4

    Minor

    The discussion identifies the three pigmentation loci as including SLC24A4, whereas its other statement of the three identified loci names SLC24A5.

  • Chromosome 15 assay interval is mislabeled as 2.4 Mb

    Minor

    The stated cohort 2 assay interval spans 2,946,727 bases, or about 2.95 Mb, rather than the 2.4 Mb stated in the table title. The 2.4-Mb description fits the narrower cohort 1 association interval, not the extended cohort 2 interval.

2 of 2

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Authors
Stokowski, R. P., Pant, P. V. K., Dadd, T., Fereday, A., Hinds, D. A., Jarman, C., Filsell, W., Ginger, R. S., Green, M. R., van der Ouderaa, F. J., & Cox, D. R.
Affiliations
  • Perlegen (United States) (US)
  • Unilever (United Kingdom) (GB)
Corresponding author
Stokowski, Renee P.
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2007-12
Volume
81
Issue
6
Pages
1119-1132
ISSN
0002-9297 (ISSN-L)
DOI
10.1086/522235
PMC
PMC2276347
OpenAlex
W1982516085
Semantic Scholar
7b5af5190410321a58e12a036725c9f3c5df7276
Cited by
315
References
57
Citations by year
2026: 12 · 2025: 13 · 2024: 18 · 2023: 6 · 2022: 12 · 2021: 12 · 2020: 17 · 2019: 12 · 2018: 25 · 2017: 25 · 2016: 20 · 2015: 14 · 2014: 23 · 2013: 20 · 2012: 20
FWCI
7.15
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
skin pigmentation, melanin content, skin reflectance, SLC24A5, TYR, SLC45A2, single nucleotide polymorphisms, South Asian populations, genetic variation
MeSH terms
Antigens, Neoplasm, Bangladesh, Gene Frequency, Humans, India, Melanins, Pakistan, Phenotype, Skin Physiological Phenomena, Skin Pigmentation, Sri Lanka, Genome, Human, Antiporters, Polymorphism, Single Nucleotide, Membrane Transport Proteins

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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