Genome-wide study of hair colour in UK Biobank explains most of the SNP heritability

Morgan, Michael D.; Pairo-Castineira, Erola; Rawlik, Konrad; Canela-Xandri, Oriol; Rees, Jonathan; Sims, David; Tenesa, Albert; Jackson, Ian J.

doi:10.1038/s41467-018-07691-z

Cited by 105 publications

(131 citation statements)

References 50 publications

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“…The MC1R locus at 16q24.3 showed evidence of a large number of SNPs (24) driving the association, suggesting, in part the presence of allelic heterogeneity 8 . This is consistent with previous studies including a recent GWAS in the UK Biobank, which found 31 SNPs independently associated with red hair color near MC1R, of which only 10 were coding variants 9,10 . Due to allelic complexity and potential artifacts with an external LD reference panel, this locus was also excluded from conditional analysis.…”

supporting

confidence: 93%

Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma

et al. 2020

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Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility.

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supporting

confidence: 93%

Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma

et al. 2020

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“…We also found that skin expression of the genes PKHD1 and TSPAN10 previously reported as associated with hair colour [21], but which were not part of this study, was associated with ease of skin tanning, black hair, and skin colour, at the multiple comparisons corrected p-value.…”

Section: Summary Data-based Mendelian Randomization (Smr) Of Gene Expsupporting

confidence: 66%

“…Although sample sizes were modest, we detected a strong inverse association of red hair with cg07402062, which is located in the gene SPIRE2 (MC1R region). Interestingly, a recent GWAS of hair colour has identified the strongest genetic signal of association with red hair (vs brown/black hair) at SNP rs34357723 (T allele associated with red hair; LD with rs1805007, r 2 = 0.27), a signal that remained relevant even after adjustment for MC1R coding variants [21]. Rs34357723 is an intronic variant of SPIRE2, and GoDMC data indicates that it is also a strong mQTL for cg07402062, explaining ~16% of DNAm at this site (T allele beta = -0.82, se = 0.01).…”

Section: Discussionmentioning

confidence: 99%

Investigating DNA methylation as a potential mediator between pigmentation genes, pigmentary traits and skin cancer

Bonilla

Bertoni

Min

et al. 2020

Preprint

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BackgroundIncidence rates for melanoma and non-melanoma skin cancer (NMSC), which includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), have been steadily increasing in all populations. Populations of European ancestry exhibit the highest rates and therefore, have been widely studied. Pigmentation characteristics are well-known risk factors for skin cancer, particularly fair skin, red hair, blue eyes and the inability to tan. Polymorphisms in established pigmentation-related genes have been associated with these traits and with an increased risk of malignancy. However, the functional relationship between genetic variation and disease is still unclear, with the exception of red hair colour variants in the melanocortin 1 receptor (MC1R) gene. ObjectivesThe aim of this study was to explore the possibility that non-coding pigmentation SNPs are associated with pigmentary traits and skin cancer via DNA methylation (DNAm). Methods and ResultsUsing a meta-GWAS of whole blood DNAm from 36 European cohorts (N=27,750; the Genetics of DNA Methylation Consortium, GoDMC), we found that 19 out of 27 pigmentation-associated SNPs distributed within 10 genes (ASIP, BNC2, IRF4, HERC2, MC1R, OCA2, SLC24A4, SLC24A5, SLC45A2, TYR) were associated with 391 DNAm sites across 30 genomic regions. We selected 25 DNAm sites for further analysis.We examined the effect of the chosen DNAm sites on pigmentation traits, sun exposure phenotypes, and skin cancer, and on gene expression in whole blood. We found an association of decreased DNAm at cg07402062 with red hair in the Avon Longitudinal Study of Parents and Children (ALSPAC), and a strong positive association of DNAm at this and correlated sites with higher expression of SPIRE2. Additionally, we investigated the association of gene expression in skin with pigmentation traits and skin cancer. The expression of ASIP, FAM83C, NCOA6, CDK10, and EXOC2 was associated with hair colour, whilst that of ASIP and CDK10 also had an effect on melanoma and BCC. ConclusionsOur results indicate that DNAm and expression of genes in the 16q24.3 and 20q11.22 regions, deserve to be further investigated as potential mediators of the relationship between genetic variants, pigmentation/sun exposure phenotypes, and some types of skin cancer.We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses.

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“…GWAS studies have identified over 800 SNPs associated with human pigmentation variation and melanocyte-related phenotypes [84][85][86]. Most GWAS SNPs reside in non-coding regions [19,82,83] and are hypothesized to reside in cis-regulatory regions or in close linkage disequilibrium (LD) to causative SNPs located within cis-regulatory regions.…”

Section: Discussionmentioning

confidence: 99%

“…with melanocyte phenotypes resided within our collection of melanocyte lineage distal enhancer elements. The H3K27ac-marked regions in 501mel cells were compared to 814 SNPs that have been previously implicated in human pigmentation and/or melanoma through GWAS [84][85][86]. These comparisons identified 90 pigmentation/melanoma GWAS loci that overlap with regions of H3K27ac acetylation and/or SOX10 ChIP-Seq binding ( Table 1, Additional file 2: Table S7), thus highlighting the variants located within these regions as high priority candidates for future studies of the function of these distal enhancers.…”

Section: Azd6244 Dmsomentioning

confidence: 99%

MEK inhibition remodels the active chromatin landscape and induces SOX10 genomic recruitment in BRAF(V600E) mutant melanoma cells

Fufa

Baxter

Wedel

et al. 2019

Epigenetics & Chromatin

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Background: The MAPK/ERK signaling pathway is an essential regulator of numerous cell processes that are crucial for normal development as well as cancer progression. While much is known regarding MAPK/ERK signal conveyance from the cell membrane to the nucleus, the transcriptional and epigenetic mechanisms that govern gene expression downstream of MAPK signaling are not fully elucidated. Results: This study employed an integrated epigenome analysis approach to interrogate the effects of MAPK/ERK pathway inhibition on the global transcriptome, the active chromatin landscape, and protein-DNA interactions in 501mel melanoma cells. Treatment of these cells with the small-molecule MEK inhibitor AZD6244 induces hyperpigmentation, widespread gene expression changes including alteration of genes linked to pigmentation, and extensive epigenomic reprogramming of transcriptionally distinct regulatory regions associated with the active chromatin mark H3K27ac. Regulatory regions with differentially acetylated H3K27ac regions following AZD6244 treatment are enriched in transcription factor binding motifs of ETV/ETS and ATF family members as well as the lineage-determining factors MITF and SOX10. H3K27ac-dense enhancer clusters known as super-enhancers show similar transcription factor motif enrichment, and furthermore, these super-enhancers are associated with genes encoding MITF, SOX10, and ETV/ETS proteins. Along with genome-wide resetting of the active enhancer landscape, MEK inhibition also results in widespread SOX10 recruitment throughout the genome, including increased SOX10 binding density at H3K27acmarked enhancers. Importantly, these MEK inhibitor-responsive enhancers marked by H3K27ac and occupied by SOX10 are located near melanocyte lineage-specific and pigmentation genes and overlap numerous human SNPs associated with pigmentation and melanoma phenotypes, highlighting the variants located within these regions for prioritization in future studies. Conclusions: These results reveal the epigenetic reprogramming underlying the re-activation of melanocyte pigmentation and developmental transcriptional programs in 501mel cells in response to MEK inhibition and suggest extensive involvement of a MEK-SOX10 axis in the regulation of these processes. The dynamic chromatin changes identified here provide a rich genomic resource for further analyses of the molecular mechanisms governing the MAPK pathway in pigmentation-and melanocyte-associated diseases.

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Genome-wide study of hair colour in UK Biobank explains most of the SNP heritability

Cited by 105 publications

References 50 publications

Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma

Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma

Investigating DNA methylation as a potential mediator between pigmentation genes, pigmentary traits and skin cancer

MEK inhibition remodels the active chromatin landscape and induces SOX10 genomic recruitment in BRAF(V600E) mutant melanoma cells

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