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A Genomewide Association Study of Skin Pigmentation in a South Asian Population
Open accessAbstract
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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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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36 Own result · 20 Not checked yet · 15 Own method · 13 Own interpretation · 4 No basis given
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In the paper
“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Abstract
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > PC4,
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“The inferred cluster-membership values for a two-cluster model correlate with reported geographical ancestry.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Population Structure and Construction of Balanced Pools
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“A majority of the associated SNPs, 32 (76%) of 42, yielded P values with a significance threshold of !.05 (table 5).”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Replication of Associations in Cohort 2
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“In addition, four of the top five principal components show significant association with reported ancestry regions in an analysis of variance”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Population-Structure Correction in the Association Analysis
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“When the conditional analysis was performed in reverse, by evaluation of the association of rs1426654 in cohort 2 conditional on each of the other 407 SNPs in this region in turn, the rs1426654 association was found to be significant at the genomewide level ( ) Ϫ8 P !3.3 # 10 for all SNPs but rs1834640”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Independent Associations on Chromosome 15 in the Vicinity of SLC24A5
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“Using the same genotype data set of 294 GC SNPs and a method described elsewhere, 32,33 we found significant population stratification between the tails of the skinreflectance distribution.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Population Structure and Construction of Balanced Pools
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“by performing an association analysis conditional on the genotypes of rs1426654 in cohort 2, we observed that none of the other SNPs rise above the Bonferroni threshold for significance of conditional association in the region ( ) (fig. 3 and Ϫ4 a p 0.05/407 p 1.23 # 10 table 6).”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Independent Associations on Chromosome 15 in the Vicinity of SLC24A5
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“The single-SNP association analyses with cohorts 1 and 2 identified three nonsynonymous polymorphisms in three genes-rs1426654 (p.A111T) in SLC24A5, rs16891982 (p.L374F) in SLC45A2, and rs1042602 (p.S192Y) in TYRthat show genomewide significance for association with skin pigmentation, on the basis of a multiplicative model of risk.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Dominance and Interactions among Three Nonsynonymous Polymorphisms
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“This SNP is in strong linkage disequilibrium with the most significant SNP from the genomewide scan, rs1834640 ( ) , 2 R p 0.93”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Independent Associations on Chromosome 15 in the Vicinity of SLC24A5
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“Treating the two cohorts as a single population of 968 individuals in the association anal-ysis, instead of independently, yielded different statistical conclusions for only four SNPs, the intronic TYR SNP rs12295166 and three chromosome 15 SNPs, which show genomewide significance in the joint analysis but failed to reach statistical significance by the previous analysis (table 5).”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Replication of Associations in Cohort 2
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“After all the data-quality filters were applied, we had high-quality D or fitted D estimates for 1,502,205 ˆp p SNPs.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Pooled Genotyping Results
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“Surprisingly, 39 of the 42 associated SNPs are all located within a single 2.4-Mb chromosomal region of 15q21.1-21.2, between chromosomal positions 45,774,265 and 48,220,992.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Association Results for Cohort 1
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“We tested each of the three pairs separately and found no evidence for pairwise interactions (rs1426654-rs16891982, ; rs1426654-P p .77 rs1042602, ; rs16891982-rs1042602, ).There-P p .38 P p .12 fore, our data are most consistent with a simple model for skin pigmentation comprising additive contributions from alleles at the three associated nonsynonymous polymorphisms.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Dominance and Interactions among Three Nonsynonymous Polymorphisms
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“There is no evidence of interactions between these two SNPs in our study population ( ).”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > in an African American population (
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“rs1037208, located 4,414 bp from rs1800404, yielded the most significant joint cohort association P value ( ) of Ϫ5 P p 5.6 # 10 several OCA2 SNPs that we assayed with individual genotyping.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > in an African American population (
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“Strikingly, our primary associated SNP in SLC24A5 may explain 130% of the variance of the dichotomously defined skin reflectance in our study population.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Abstract
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Single-SNP Association Tests
What the sources say
- Not checked yetcites [24] source
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“Melanin is the major determining factor in intrinsic skin pigmentation 43 ; therefore, we were most interested in identifying genes that affect melanin.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Determination of the Phenotypic Groups
What the sources say
- Not checked yetcites [43] source
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“Recruitment of individuals for the replication population, cohort 2, was designed to reduce the population stratification bias with respect to skin reflectance, with the use of reported geographical ancestry as a marker for the genetic ancestry profiles we detected in cohort 1 (fig.2).”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Population Structure and Construction of Balanced Pools
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“On the basis of these findings, we adjusted all association analyses for the first five principal components in addition to sex.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > PC4,
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“Because our study design used the tails of the skin-reflectance distribution, we cannot directly determine the overall fraction of the trait variance in the population that is accounted for by the associated SNPs.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Dominance and Interactions among Three Nonsynonymous Polymorphisms
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“The genetic diversity within South Asian populations potentially introduces significant confounding in an association study because of population structure.45”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Population Structure and Construction of Balanced Pools
What the sources say
- Not checked yetcites [45] source
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“To control for spurious associations due to systematic differences in ancestry between the L and H groups, we composed the two DNA pools to be used in the pooled genotyping with individuals who were matched for ancestry.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Population Structure and Construction of Balanced Pools
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“Since we observed significant population stratification between the tails of the skin-reflectance distribution in this South Asian population, we assessed and adjusted for population structure in the association analysis, using the genotypes of our GC panel of 312 SNPs.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Population-Structure Correction in the Association Analysis
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“With the use of objective quantitative measurements of melanin content, our study clearly identifies three loci-TYR, SLC45A2, and SLC24A5-that contribute to the natural variation in skin pigmentation within a South Asian population.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
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“The melanin contribution to skin pigmentation can be quantitatively measured and distinguished from redness caused by hemoglobin and/or inflammation by reflectance spectrophotometry with use of the L* value from the L*a*b* color system.44”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Determination of the Phenotypic Groups
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- Not checked yetcites [44] source
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“indicating that the two probably represent a single associated locus.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Independent Associations on Chromosome 15 in the Vicinity of SLC24A5
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“This is the first genomewide association study, to our knowledge, to investigate the genetic determinants of normal skin pigmentation within a human population.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
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“The importance of these three particular SNPs-rs1042602 in TYR, rs16891982 in SLC45A2, and rs1426654 in SLC24A5-to skin-pigmentation variation within other populations is likely to be highly variable across the globe.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
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“On the basis of International HapMap data for the CEU sample (Utah residents with ancestry from northern and western Europe), 29 these two SNPs are in modest linkage disequilibrium with one another ( ).Al-2 R p 0.35”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > in an African American population (
What the sources say
- Not checked yetcites [29] source
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“Therefore, it is likely that loci other than the three identified in this study influence skin pigmentation in other global populations.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > in an African American population (
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“When taken together with the results of our study, the evidence is compelling that these three loci are a large component of the genetic influence of constitutive pigmentation in these diverse populations.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
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“Although we cannot completely exclude the possibility that multiple real independent associations exist in this chromosomal 15 region, our conditional analysis shows unambiguously that the association signals on all SNPs in the region are far less significant than those for the primary associated SNP in SLC24A5.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
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“During the past few years, several candidate-gene admixture studies on a cohort of African Americans and African Caribbeans has shown that the same three nonsynonymous polymorphisms that we found in our South Asian cohort-rs1042602 in TYR, rs16891982 in SLC45A2, and rs1426654 in SLC24A5-are significantly associated with melanin content measured by reflectometry.13,21,22,24”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
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“It is encouraging that, despite the use of a study population that is genetically diverse and a trait that is strongly confounded with ancestry, we were able to detect three true SNP associations.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
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In the paper
“The SLC24A5 SNP rs1426654 is nearly fixed for one allele in all European groups.11,13,22,29,30,51”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
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“Our analysis of population structure was based on the individual genotypes of 968 individuals with 292 unlinked SNPs.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
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“Notwithstanding the limitations imposed by the size of this data set on the detection of structure, 48 the results for these 292 SNPs indicated that we were able to adequately correct for stratification.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
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“It is important to note that the application of a very strict Bonferroni correction of 1,502,205 independent tests, combined with the pooled genotyping design, greatly reduces the power of this study to detect real SNP associations with small effects on skin pigmentation”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > in an African American population (
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“thus, it is possible that loci other than TYR, SLC45A2, and SLC24A5 may affect skin-pigmentation variation within the South Asian population.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > in an African American population (
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“Since the previous association showed significant association with only female, but not male, skin pigmentation, our pooled genotyping strategy that used mixed sexes would not have the power to find such an association.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > in an African American population (
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“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).”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Association Results for Cohort 1
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“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).”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Independent Associations on Chromosome 15 in the Vicinity of SLC24A5
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“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 .”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Association Results for Cohort 1
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“The first and fifth components showed significant associations ( and , Ϫ22 Ϫ3 P p 4.6 # 10 P p 1.7 # 10 respectively).”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > PC4,
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Independent Associations on Chromosome 15 in the Vicinity of SLC24A5
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Dominance and Interactions among Three Nonsynonymous Polymorphisms
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“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).”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Population Structure and Construction of Balanced Pools
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Population-Structure Correction in the Association Analysis
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“This SNP, rs1834640, is located 21 kb from the closest gene, SLC24A5.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Association Results for Cohort 1
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Individual Genotyping for Cohort 1
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“The last associated SNP, rs16891982, is also a nonsynonymous polymorphism (p.L374F) in the gene SLC45A2 on chromosome 5.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Association Results for Cohort 1
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“These included the nonsynonymous polymorphisms in TYR and SLC45A2, as well as 30 SNPs in the 2.4-Mb region on chromosome 15.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Replication of Associations in Cohort 2
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Population Structure and Construction of Balanced Pools
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“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).”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Independent Associations on Chromosome 15 in the Vicinity of SLC24A5
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Replication of Associations in Cohort 2
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“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).”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Population Structure and Construction of Balanced Pools
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“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”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Population Structure and Construction of Balanced Pools
What the sources say
- Not checked yetcites [46] source
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Dominance and Interactions among Three Nonsynonymous Polymorphisms
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > in an African American population (
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > in an African American population (
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Abstract
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“Epidemiological studies in humans show that skin pigmentation is a polygenic quantitative trait with high heritability, [8][9][10]”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Abstract
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Population-Structure Correction in the Association Analysis
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“Human skin color is largely determined by two biological components, melanin and hemoglobin, and one major environmental component, exposure to UV light.42”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Determination of the Phenotypic Groups
What the sources say
- Not checked yetcites [42] source
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Single-SNP Association Tests
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Determination of the Phenotypic Groups
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- Not checked yetcites [41] source
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Association Results for Cohort 1
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Determination of the Phenotypic Groups
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Individual Genotyping for Cohort 1
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Single-SNP Association Tests
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In the paper
“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Independent Associations on Chromosome 15 in the Vicinity of SLC24A5
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“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).”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Independent Associations on Chromosome 15 in the Vicinity of SLC24A5
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > 4 3 5 6 5
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
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“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”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
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- Not checked yetcites [20] source
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“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > in an African American population (
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
What the sources say
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
What the sources say
- Not checked yetcites [22] source
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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.”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > in an African American population (
What the sources say
- Not checked yetcites [17] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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.”
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?
In the citing paper
“However, although there is strong evidence that the derived HERC2 rs12913832 G allele is recessive (36), it is less clear whether the SLC45A2 and TYR derived alleles are codominant, recessive, or dominant (22, 35).”
From Direct evidence for positive selection of skin, hair, and eye pigmentation in Europeans during the last 5,000 y (2014) · cites this paper as [35]
In the citing paper
“Recent studies have also suggested additive contributions of MATP and NCKX5 to human skin coloration (Stokowski et al., 2007).”
From Analysis of Cultured Human Melanocytes Based on Polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P Loci (2009) · cites this paper as Stokowski et al., 2007
In the citing paper
“We identified a non-synonymous single nucleotide polymorphism (nsSNP) 2 in the SLC24A5 gene (rs1426654) that was previously unknown to skin pigmentation biologists.”
From SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium-calcium exchange activity that regulates human epidermal melanogenesis (2008) · cites this paper as [6]
In the citing paper
“A non-synonymous single nucleotide polymorphism in the human SLC24A5 gene is associated with natural human skin color variation.”
From SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium-calcium exchange activity that regulates human epidermal melanogenesis (2008) · cites this paper as [6]
In the citing paper
“Using high density whole genome array technology, we have defined the key genetic variants associated with natural skin color variation in a population of South Asian ancestry (6).”
From SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium-calcium exchange activity that regulates human epidermal melanogenesis (2008) · cites this paper as [6]
In the citing paper
“In this study, three genes, SLC24A5, SLC45A2, and TYR were found to explain a large fraction of the pigmentation difference among individuals with high and low skin reflectance.”
From Genome-Wide Association Studies of Quantitatively Measured Skin, Hair, and Eye Pigmentation in Four European Populations (2012) · cites this paper as [17]
In the citing paper
“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.”
From Genome-Wide Association Studies of Quantitatively Measured Skin, Hair, and Eye Pigmentation in Four European Populations (2012) · cites this paper as [17]
In the citing paper
“The SLC24A5 gene has been identified as the principal regulator of skin pigmentation diversity within South Asia, particularly rs1426654, whose derived A allele, almost fixed in Europeans, shows a broad frequency range across South Asian populations and is strongly associated with lighter skin and reduced melanin levels ( Stokowski et al., 2007 ; Basu Mallick et al., 2013 ; Mishra et al., 2017 ).”
From The genetic architecture of human skin pigmentation: evolution and adaptation across global populations (2026) · cites this paper as Stokowski et al., 2007
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
“the three loci (TYR, SLC24A4, and SLC45A2).”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
“three loci-TYR, SLC45A2, and SLC24A5-that contribute to the natural variation in skin pigmentation within a South Asian population.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Discussion
“Table 6.Association Test Results for a 2.4-Mb Region on Chromosome 15 for Cohort 2”
§ A Genomewide Association Study of Skin Pigmentation in a South Asian Population > Independent Associations on Chromosome 15 in the Vicinity of SLC24A5
“The range for SNP selection was extended by 0.25 Mb in both directions from the boundaries established by significant cohort 1 associations in the region-that is, from positions 45,524,265 to 48,470,992 on chromosome 15.”
Citations
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Initial sequencing and analysis of the human genome
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The sequence of the human genome
Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J., Sutton, G. G., Smith, H. O., Yandell, M., Evans, C. A., Holt, R. A., et al. (2001) · Science · doi:10.1126/science.1058040 · Cited by 13,909
Principal components analysis corrects for stratification in genome-wide association studies
Price, A. L., Patterson, N. J., Plenge, R. M., Weinblatt, M. E., Shadick, N. A., & Reich, D. (2006) · Nature Genetics · doi:10.1038/ng1847 · Cited by 10,248
A haplotype map of the human genome
The International HapMap Consortium (2005) · Nature · doi:10.1038/nature04226 · Cited by 5,858
Population Structure and Eigenanalysis
Patterson, N., Price, A. L., & Reich, D. (2006) · PLoS Genetics · doi:10.1371/journal.pgen.0020190 · Cited by 5,280
Genomic Control for Association Studies
Devlin, B., & Roeder, K. (1999) · Biometrics · doi:10.1111/j.0006-341x.1999.00997.x · Cited by 3,162 · cited 2×
“.001 for SNPs that were also statistically significant at a level of P on a simple trend test for association with skin reflectance.001 corrected with GC.39 For these potentially associated SNPs, the clustering was visually inspected, and SNPs were excluded from further analysis if problems were detected.”
A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms
The International SNP Map Working Group, Laboratories:, C. S. H., Sachidanandam, R., Weissman, D., Schmidt, S. C., Kakol, J. M., Stein, L. D., National Center for Biotechnology Information:, Marth, G., Sherry, S., et al. (2001) · Nature · doi:10.1038/35057149 · Cited by 2,977
Use of Unlinked Genetic Markers to Detect Population Stratification in Association Studies
Pritchard, J. K., & Rosenberg, N. A. (1999) · The American Journal of Human Genetics · doi:10.1086/302449 · Cited by 1,198
Whole-Genome Patterns of Common DNA Variation in Three Human Populations
Hinds, D. A., Stuvé, L. L., Nilsen, G. B., Halperin, E., Eskin, E., Ballinger, D. G., Frazer, K. A., & Cox, D. (2005) · Science · doi:10.1126/science.1105436 · Cited by 1,179
Self-citation
Cited by
Sorted by citations
Genome-wide association study of 107 phenotypes in Arabidopsis thaliana inbred lines
Atwell, S., Huang, Y. S., Vilhjálmsson, B. J., Willems, G., Horton, M., Li, Y., Meng, D., Platt, A., Tarone, A. M., Hu, T. T., et al. (2010) · Nature · doi:10.1038/nature08800 · Cited by 1,780
Human Demographic History Impacts Genetic Risk Prediction across Diverse Populations
Martin, A. R., Gignoux, C. R., Walters, R. K., Wojcik, G. L., Neale, B. M., Gravel, S., Daly, M. J., Bustamante, C. D., & Kenny, E. E. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.03.004 · Cited by 1,391
Ancient human genomes suggest three ancestral populations for present-day Europeans
Lazaridis, I., Patterson, N., Mittnik, A., Renaud, G., Mallick, S., Kirsanow, K., Sudmant, P. H., Schraiber, J. G., Castellano, S., Lipson, M., et al. (2014) · Nature · doi:10.1038/nature13673 · Cited by 1,357
Human genetic variation and its contribution to complex traits
Frazer, K. A., Murray, S. S., Schork, N. J., & Topol, E. J. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2554 · Cited by 1,073
A HapMap harvest of insights into the genetics of common disease
Manolio, T. A., Brooks, L. D., & Collins, F. S. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34772 · Cited by 889
Metadata
- 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.
- 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)
- 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
- bronze
- doi.org
- 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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