Investigating DNA methylation as a potential mediator between pigmentation genes, pigmentary traits and skin cancer
Josine L. Min,
Genetics of DNA Methylation Consortium,
Hannah R Elliott
Posted 30 Apr 2020
bioRxiv DOI: 10.1101/2020.04.29.060566 (published DOI: 10.1111/pcmr.12948)
Posted 30 Apr 2020
Background: Incidence 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. Objectives: The 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 Results: Using 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. Conclusions: Our 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. ### Competing Interest Statement The authors have declared no competing interest.
- Downloaded 367 times
- Download rankings, all-time:
- Site-wide: 90,479
- In genetics: 3,856
- Year to date:
- Site-wide: 61,987
- Since beginning of last month:
- Site-wide: 41,476
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!