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Meta-analysis and prioritization of human skin pigmentation-associated GWAS-SNPs using ENCODE data-based web-tools

  • Kausik Ganguly
  • Tania Saha
  • Arpan Saha
  • Tithi Dutta
  • Souradeep Banerjee
  • Debmalya Sengupta
  • Sreyashi Bhattacharya
  • Sampurna Ghosh
  • Mainak SenguptaEmail author
Original Paper

Abstract

Skin pigmentation in human is a complex trait, which varies widely, both within and between human populations. The exact players governing the trait of skin pigmentation remain elusive till date. Various Genome Wide Association Studies (GWAS) have shown the association of different genomic variants with normal human skin pigmentation, often indicating genes with no direct implications in melanin biosynthesis or distribution. Little has been explained in terms of the functionality of the associated Single-Nucleotide Polymorphisms (SNPs) with respect to modulating the skin pigmentation phenotype. In the present study, which, to our knowledge, is the first of its kind, we tried to analyze and prioritize 519 non-coding SNPs and 24 3′UTR SNPs emerging from 14 different human skin pigmentation-related GWAS, primarily using several ENCODE-based web-tools like rSNPBase, RegulomeDB, HaploReg, etc., most of which incorporate experimentally validated evidences in their predictions. Using this comprehensive, in-silico, analytical approach, we successfully prioritized all the pigmentation-associated GWAS-SNPs and tried to annotate pigmentation-related functionality to them, which would pave the way for deeper understanding of the molecular basis of human skin pigmentation variations.

Keywords

Pigmentation GWAS ENCODE SNP Melanin 

Notes

Acknowledgements

The study was supported by funding from Department of Science and Technology-Promotion of University Research and Scientific Excellence (DST-PURSE), Government of India. K Ganguly is supported by Senior Research Fellowship from Council of Scientific & Industrial Research (CSIR), India, provided to Department of Genetics, University of Calcutta. T Saha and D Sengupta are supported by Senior Research Fellowship from University Grants Commission, Government of India.

Funding

This study has been partially supported by: The Department of Science and Technology (DST), Government of India, Promotion of University Research and Scientific Excellence (DST-PURSE) provided to University of Calcutta. K. Ganguly is supported by Senior Research Fellowship (SRF) from Council of Scientific & Industrial Research (CSIR), Human Resource Development Group, Government. of India. T. Saha and D. Sengupta are supported by Senior Research Fellowships (SRF) from University Grants Commission (UGC), Govt. of India.

Compliance with ethical standards

Conflict of interest

All the authors gave approval for submission of the current version of the manuscript for publication and have full access to the study data. Authors declare no conflict of interest with respect to this article.

Ethical approval and informed consent from patients

Not applicable for this study.

Supplementary material

403_2019_1891_MOESM1_ESM.pdf (373 kb)
Supplementary material 1 (PDF 373 KB)
403_2019_1891_MOESM2_ESM.pdf (264 kb)
Supplementary material 2 (PDF 263 KB)

References

  1. 1.
    Boyle AP, Hong EL, Hariharan M et al (2012) Annotation of functional variation in personal genomes using RegulomeDB. Genome Research 22(9):1790–1797CrossRefGoogle Scholar
  2. 2.
    Buffey JA, Edgecombe M, Mac Neil S (1993) Calcium plays a complex role in the regulation of melanogenesis in murine B16 melanoma cells. Pigment Cell Res 6(6):385–393CrossRefGoogle Scholar
  3. 3.
    Candille SI, Absher DM, Beleza S et al (2012) Genome-wide association studies of quantitatively measured skin, hair, and eye pigmentation in four European populations. PLoS One 7(10):e48294.  https://doi.org/10.1371/journal.pone.0048294 CrossRefGoogle Scholar
  4. 4.
    Carithers LJ, Ardlie K, Barcus M et al (2015) A novel approach to high-quality postmortem tissue procurement: the GTEx Project. Biopreserv Biobank 13(5):311–319.  https://doi.org/10.1089/bio.2015.0032 CrossRefGoogle Scholar
  5. 5.
    Chuamanochan M, Haws AL, Pattanaprichakul P (2015) Reticulate hyperpigmentation in systemic sclerosis: a case report and review of the literature. J Med Case Rep 9:219.  https://doi.org/10.1186/s13256-015-0697-2 CrossRefGoogle Scholar
  6. 6.
    Clark P, Stark AE, Walsh RJ, Jardine R, Martin NG (1981) A twin study of skin reflectance. Ann Hum Biol 8(6):529–541CrossRefGoogle Scholar
  7. 7.
    Crawford NG, Kelly DE, Hansen MEB et al. (2017) Loci associated with skin pigmentation identified in African populations. Science.  https://doi.org/10.1126/science.aan8433 Google Scholar
  8. 8.
    Dalziel M, Kolesnichenko M, das Neves RP, Iborra F, Goding C, Furger A (2011) Alpha-MSH regulates intergenic splicing of MC1R and TUBB3 in human melanocytes. Nucleic Acids Res 39(6):2378–2392.  https://doi.org/10.1093/nar/gkq1125 CrossRefGoogle Scholar
  9. 9.
    ENCODE Project Consortium1 (2011) A user’s guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol 9(4):e1001046.  https://doi.org/10.1371/journal.pbio.1001046 CrossRefGoogle Scholar
  10. 10.
    ENCODE Project Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489(7414):57–74.  https://doi.org/10.1038/nature11247 CrossRefGoogle Scholar
  11. 11.
    Eriksson N, Macpherson JM, Tung JY et al (2010) Web-based, participant-driven studies yield novel genetic associations for common traits. PLoS Genet 6(6):e1000993.  https://doi.org/10.1371/journal.pgen.1000993 CrossRefGoogle Scholar
  12. 12.
    Frändberg PA1, Doufexis M, Kapas S, Chhájlani V (1998) Human pigmentation phenotype: a point mutation generates nonfunctional MSH receptor. Biochem Biophys Res Commun 245(2):490–492.  https://doi.org/10.1006/bbrc.1998.8459 CrossRefGoogle Scholar
  13. 13.
    Frisancho AR, Wainwright R, Way A (1981) Heritability and components of phenotypic expression in skin reflectance of Mestizos from the Peruvian lowlands. Am J Phys Anthropol 55(2):203–208.  https://doi.org/10.1002/ajpa.1330550207 CrossRefGoogle Scholar
  14. 14.
    Gao L, Emond MJ, Louie T et al (2016) Whole-exome sequencing identifies rare variants in ATP8B4 as a risk factor for systemic sclerosis. Arthritis Rheumatol 68(1):191–200.  https://doi.org/10.1002/art.39449 CrossRefGoogle Scholar
  15. 15.
    Gerstenblith MR, Shi J, Landi MT (2010) Genome-wide association studies of pigmentation and skin cancer: a review and meta-analysis. Pigment Cell Melanoma Res 23(5):587–606.  https://doi.org/10.1111/j.1755-148X.2010.00730.x CrossRefGoogle Scholar
  16. 16.
    GTEx Consortium (2013) The genotype-tissue expression (GTEx) project. Nat Genet 2013;45(6):580–585.  https://doi.org/10.1038/ng.2653 CrossRefGoogle Scholar
  17. 17.
    Guo L, Du Y, Chang S, Zhang K, Wang J (2014) rSNPBase: a database for curated regulatory SNPs. Nucleic Acids Res 42:D1033–D1039.  https://doi.org/10.1093/nar/gkt1167 CrossRefGoogle Scholar
  18. 18.
    Harrison GA, Owen JJ (1964) Studies on the inheritance of human skin colour. Ann Hum Genet 28:27–37CrossRefGoogle Scholar
  19. 19.
    Han J, Kraft P, Nan H et al (2008) A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation. PLoS Genet 4(5):e1000074.  https://doi.org/10.1371/journal.pgen.1000074 CrossRefGoogle Scholar
  20. 20.
    Hernandez-Pacheco N, Flores C, Alonso S (2017) Identification of a novel locus associated with skin colour in African-admixed populations. Sci Rep 7:44548.  https://doi.org/10.1038/srep44548. et al.CrossRefGoogle Scholar
  21. 21.
    Herraiz C, Olivares C, Castejón-Griñán M et al (2015) Functional characterization of MC1R-tubb3 intergenic splice variants of the human melanocortin 1 receptor. PLoS One 10(12):e0144757.  https://doi.org/10.1371/journal.pone.0144757 CrossRefGoogle Scholar
  22. 22.
    Kenny EE, Timpson NJ, Sikora M et al (2012) Melanesian blond hair is caused by an amino acid change in TYRP1. Science 336(6081):554.  https://doi.org/10.1126/science.1217849 CrossRefGoogle Scholar
  23. 23.
    Kodani A, Yu TW, Johnson JR et al (2015) Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication. Elife.  https://doi.org/10.7554/eLife.07519 Google Scholar
  24. 24.
    Lai X, Wichers HJ, Soler-Lopez M, Dijkstra BW (2017) Structure of human tyrosinase related protein 1 reveals a binuclear zinc active site important for melanogenesis. Angew Chem Int Ed Engl 56(33):9812–9815.  https://doi.org/10.1002/anie.201704616 CrossRefGoogle Scholar
  25. 25.
    Liu F, Visser M, Duffy DL et al (2015) Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up. Hum Genet 134(8):823–835.  https://doi.org/10.1007/s00439-015-1559-0 CrossRefGoogle Scholar
  26. 26.
    MacArthur J, Bowler E, Cerezo M et al (2017) The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog). Nucleic Acids Res 45(D1):D896–D901.  https://doi.org/10.1093/nar/gkw1133 CrossRefGoogle Scholar
  27. 27.
    Madej MG, Dang S, Yan N, Kaback HR (2013) Evolutionary mix-and-match with MFS transporters. Proc Natl Acad Sci USA 110(15):5870–5874.  https://doi.org/10.1073/pnas.1303538110 CrossRefGoogle Scholar
  28. 28.
    Martin AR, Lin M, Granka JM3 et al (2017) An unexpectedly complex architecture for skin pigmentation in Africans. Cell 171(6):1340–1353.e14.  https://doi.org/10.1016/j.cell.2017.11.015 CrossRefGoogle Scholar
  29. 29.
    McNiven MA, Ward JB (1988) Calcium regulation of pigment transport in vitro. J Cell Biol 106(1):111–125CrossRefGoogle Scholar
  30. 30.
    Méhul B, Bernard D, Schmidt R (2001) Calmodulin-like skin protein: a new marker of keratinocyte differentiation. J Invest Dermatol 116(6):905–909.  https://doi.org/10.1046/j.0022-202x.2001.01376.x CrossRefGoogle Scholar
  31. 31.
    Melé M, Ferreira PG, Reverter F et al (2015) Human genomics. The human transcriptome across tissues and individuals. Science 348(6235):660–665.  https://doi.org/10.1126/science.aaa0355 CrossRefGoogle Scholar
  32. 32.
    Nan H, Kraft P, Qureshi AA et al (2009) Genome-wide association study of tanning phenotype in a population of European ancestry. J Invest Dermatol 129(9):2250–2257.  https://doi.org/10.1038/jid.2009.62 CrossRefGoogle Scholar
  33. 33.
    Rooryck C, Roudaut C, Robine E, Müsebeck J, Arveiler B (2006) Oculocutaneous albinism with TYRP1 gene mutations in a Caucasian patient. Pigment Cell Res 19(3):239–242.  https://doi.org/10.1111/j.1600-0749.2006.00298.x CrossRefGoogle Scholar
  34. 34.
    Rouillard AD, Gundersen GW, Fernandez NF et al., (2016) The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database (Oxford).  https://doi.org/10.1093/database/baw100 Google Scholar
  35. 35.
    Sarkar A, Nandineni MR (2018) Association of common genetic variants with human skin color variation in Indian populations. Am J Hum Biol.  https://doi.org/10.1002/ajhb.23068 Google Scholar
  36. 36.
    Sloan CA, Chan ET, Davidson JM et al (2016) ENCODE data at the ENCODE portal. Nucleic Acids Res 44(D1):D726–D732.  https://doi.org/10.1093/nar/gkv1160 CrossRefGoogle Scholar
  37. 37.
    Smith-Thomas L, Haycock JW, Metcalfe R et al (1998) Involvement of calcium in retinal pigment epithelial cell proliferation and pigmentation. Curr Eye Res 17(8):813–822CrossRefGoogle Scholar
  38. 38.
    Szklarczyk D, Franceschini A, Wyder S, et al (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43(Database issue):D447–D452.  https://doi.org/10.1093/nar/gku1003 CrossRefGoogle Scholar
  39. 39.
    Stokowski RP, Pant PV, Dadd T et al (2007) A genomewide association study of skin pigmentation in a South Asian population. Am J Hum Genet 81(6):1119–1132.  https://doi.org/10.1086/522235 CrossRefGoogle Scholar
  40. 40.
    Sulem P, Gudbjartsson DF, Stacey SN et al (2007) Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat Genet 39(12):1443–1452.  https://doi.org/10.1038/ng.2007.13 CrossRefGoogle Scholar
  41. 41.
    Sulem P, Gudbjartsson DF, Stacey SN et al (2008) Two newly identified genetic determinants of pigmentation in Europeans. Nat Genet 40(7):835–837.  https://doi.org/10.1038/ng.160 CrossRefGoogle Scholar
  42. 42.
    Thomas DJ, Rosenbloom KR, Clawson H et al (2007) The ENCODE Project at UC Santa Cruz. Nucleic Acids Res. 35(Database issue):D663–D667.  https://doi.org/10.1093/nar/gkl1017 CrossRefGoogle Scholar
  43. 43.
    Ward LD, Kellis M (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40(Database issue):D930–D934.  https://doi.org/10.1093/nar/gkr917 CrossRefGoogle Scholar
  44. 44.
    Ward LD, Kellis M (2016) HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res 44(D1):D877–D881.  https://doi.org/10.1093/nar/gkv1340 CrossRefGoogle Scholar
  45. 45.
    Zhang M, Song F, Liang L et al (2013) Genome-wide association studies identify several new loci associated with pigmentation traits and skin cancer risk in European Americans. Hum Mol Genet 22(14):2948–2959.  https://doi.org/10.1093/hmg/ddt142 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of GeneticsUniversity of CalcuttaKolkataIndia

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