Human Genetics

, 122:311 | Cite as

Multilocus OCA2 genotypes specify human iris colors

  • Tony FrudakisEmail author
  • Timothy Terravainen
  • Matthew Thomas
Original Investigation


Human iris color is a quantitative, multifactorial phenotype that exhibits quasi-Mendelian inheritance. Recent studies have shown that OCA2 polymorphism underlies most of the natural variability in human iris pigmentation but to date, only a few associated polymorphisms in this gene have been described. Herein, we describe an iris color score (C) for quantifying iris melanin content in-silico and undertake a more detailed survey of the OCA2 locus (n = 271 SNPs). In 1,317 subjects, we confirmed six previously described associations and identified another 27 strongly associated with C that were not explained by continental population stratification (OR 1.5–17.9, P = 0.03 to <0.001). Haplotype analysis with respect to these 33 SNPs revealed six haplotype blocks and 11 hap-tags within these blocks. To identify genetic features for best-predicting iris color, we selected sets of SNPs by parsing P values among possible combinations and identified four discontinuous and non-overlapping sets across the LD blocks (p-Selected SNP sets). In a second, partially overlapping sample of 1,072, samples with matching diplotypes comprised of these p-Selected OCA2 SNPs exhibited a rate of C concordance of 96.3% (n = 82), which was significantly greater than that obtained from randomly selected samples (62.6%, n = 246, P<0.0001). In contrast, the rate of C concordance using diplotypes comprised of the 11 identified hap-tags was only 83.7%, and that obtained using diplotypes comprised of all 33 SNPs organized as contiguous sets along the locus (defined by the LD block structure) was only 93.3%. These results confirm that OCA2 is the major human iris color gene and suggest that using an empirical database-driven system, genotypes from a modest number of SNPs within this gene can be used to accurately predict iris melanin content from DNA.


Melanin Content Color Score Iris Color Ancestry Informative Marker Iris Pigmentation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Shannon Boyd and Sara Barrow for assistance with genotyping and Mark Shriver and Marc Bauchet of the Pennsylvania State University for assistance in collecting samples. Our work was supported with private funds.

Supplementary material


  1. Abbott C, Jackson I, Carritt B, Povey S (1991) The human homolog of the mouse brown gene maps to the short arm of chromosome 9 and extends the known region of homology with mouse chromosome 4. Genomics 11:471–473PubMedCrossRefGoogle Scholar
  2. Akey J, Wang H, Xiong M, Wu H, Liu W, Shriver M, Jin L (2001) Interaction between the melanocortin-1 receptor and P genes contributes to inter-individual variation in skin pigmentation phenotypes in a Tibetan population. Hum Genet 108:516–520PubMedCrossRefGoogle Scholar
  3. Barrett J, Fry B, Maller J, Daly M (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265PubMedCrossRefGoogle Scholar
  4. Bernstein F (1931) Die Geographische verteilung der blutgruppen und ihre anthropologische bedeutung. in Comitato Italiano per lo Studio dei Problemi Della Populazione. Roma Instituto Poligrafico dello stato. pp 227–243Google Scholar
  5. Bild A, Yao G, Chang J, Wang Q, Potti A, Chasse D, Joshi M, Harpole D, Lancaster J, Berchuck A, Olson J, Marks J, Dressman H, West M, Nevins J (2006) Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439:353–357PubMedCrossRefGoogle Scholar
  6. Bito L, Matheny A, Cruickshanks K, Nondahl D, Carino O (1997) Iris color changes past early childhood. The Louisville Twin Study. Arch Ophthalmol 115:659–663PubMedGoogle Scholar
  7. Boissy R, Zhao H, Og W, Austin L, Wildenberg S, Boissy Y, Zhao Y, Sturm R, Hearing V, King R, Nordlund J (1996) Mutation in and lack of expression of tyrosinase-related protein-1 (TRP-1) in melanocytes from an individual with brown oculocutaneous albinism: a new subtype of albinism classified as ‘OCA3.’ Am J Hum Genet 58:1145–1156PubMedGoogle Scholar
  8. Bonilla C, Parra E, Pfaff C, Dios S, Marshall J, Hamman R, Ferrell R, Hoggart C, McKeigue P, Shriver M (2004) Admixture in the Hispanics of the san luis valley Colorado, and its implications for complex trait gene mapping. Ann Hum Genet 68:139–153PubMedCrossRefGoogle Scholar
  9. Box N, Wyeth J, O’Gorman L, Martin N, Sturm R (1997) Characterization of melanocyte stimulating hormone variant alleles in twins with red hair. Hum Mol Genet 6:1891–1897PubMedCrossRefGoogle Scholar
  10. Box N, Duffy D, Irving R, Russell A, Chen W, Griffyths L, Parsons P, Green A, Sturm R (2001) Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma. J Invest Dermatol 116:224–229PubMedCrossRefGoogle Scholar
  11. Brauer G, Chopra V (1978) Estimation of the heritability of hair and iris color. Anthropol Anz 36:109–20PubMedGoogle Scholar
  12. Brilliant M (2001) The mouse p (pink-eyed dilution) and human P genes, oculocutaneous albinism type 2 (OCA2), and melanosomal pH. Pigment Cell Res 14:86–93PubMedCrossRefGoogle Scholar
  13. Brues A (1975) Rethingking human pigmentation. Am J Phys Anthropol 43:387–391PubMedCrossRefGoogle Scholar
  14. Cavalli-Sforza L, Bodmer W (1999) The genetics of human populations. Dover, Mineola pp 45–59Google Scholar
  15. Chakraborty R (1986) Gene admixture in human populations: models and predictions. Yearbook Phys Anthropol 29:1–43CrossRefGoogle Scholar
  16. Chintamaneni C, Ramsay M, Colman M, Fox M, Pickard R, Kwon B (1991) Mapping the human CAS2 gene, the homologue of the mouse brown (b) locus, to human chromosome 9p22-pter. Biochem Biophys Res Commun 178:227–235PubMedCrossRefGoogle Scholar
  17. Choudhry S, Coyle N, Tang H, Salari K, Lind D, Clark S, Tsai H, Naqvi M, Phong A, Ung N, Matallana H, Avila P, Casal J, Torres A, Nazario S, Castro R, Battle N, Perez-Stable E, Kwok P, Sheppard D, Shriver M, Rodriguez-Cintron W, Risch N, Ziv E, Buchard E (2006) Population stratification confounds genetic association studies among Latinos. Hum Genet 118:652–664PubMedCrossRefGoogle Scholar
  18. Devilly G (2005) The odds ratio generator for windows: version 1.0 (computer programme). Centre for Neuropsychology, Swinburne University, AustraliaGoogle Scholar
  19. Duffy D, Montgomery G, Chen W, Zhao Z, Le L, James M, Hayward N, Martin N, Sturm R (2007) A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation. Am J Hum Genet 80(2):241–52PubMedCrossRefGoogle Scholar
  20. Durham-Pierre D, Gardner J, Nakatsu Y, King R, Francke U, Ching A, Aquaron R, del Marmol V, Brilliant M (1994) African origin of an intragenic deletion of the human P gene in tyrosinase positive oculocutaneous albinism. Nat Genet 7:176–179PubMedCrossRefGoogle Scholar
  21. Durham-Pierre D, King R, Naber J, Laken S, Brilliant M (1996) Estimation of carrier frequency of a 2.7 kb deletion allele of the P gene associated with OCA2 in African-Americans. Hum Mutat 7:370–373PubMedCrossRefGoogle Scholar
  22. Eiberg H, Mohr J (1996) Assignment of genes coding for brown iris colour (BEY2) and brown hair colour (HCL3) on chromosome 15q. Eur J Hum Genet 4:237–241PubMedGoogle Scholar
  23. Fernandez J, Shriver M, Beasley M, Rafla-Demetrious N, Parra E, Albu J, Nicklas B, Ryan A, McKeigue P, Hoggart C, Weinsier R, Alliston D (2003) Association of African genetic admixture with resting metabolic rate and obesity among women. Obes Res 11:904–911PubMedGoogle Scholar
  24. Flanagan N, Healy E, Ray A, Philips S, Todd C, Jackson I., Birch-Machin M, Rees J (2000) Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation. Hum Molec Genet 9:2531–2537PubMedCrossRefGoogle Scholar
  25. Frudakis T, Thomas M, Gaskin Z, Venkateswarlu K, Chandra S, Ginjupalli S, Gunturi S, Natrajan S, Ponnuswamy V, Ponnuswamy K (2003) Sequences associated with human iris pigmentation. Genetics 165:2071–2083PubMedGoogle Scholar
  26. Frudakis T (2005) Powerful but requiring caution: genetic tests of ancestral origins. Nat General Soc Quart 93:260–268Google Scholar
  27. Frudakis T (2007) Molecular Photofitting: the inference of phenotype from DNA. Elsiever/Academic, New York (in press)Google Scholar
  28. Gardner J, Nakatsu Y, Gondo Y, Lee S, Lyon M, King R, Brilliant M (1992) The mouse pink-iris dilution gene: association with human Prader-Willi and Angelman syndromes. Science 257:1121–1124PubMedCrossRefGoogle Scholar
  29. Halder I, Shriver M, Thomas M, Fernandez J, Frudakis T (2006) A panel of ancestry informative markers for estimating individual biogeographical ancestry and admixture from four continents: utility and applications. Hum Genet (In review)Google Scholar
  30. Hamabe J, Fukushima Y, Harada N, Abe K, Matsuo N, Nagai T, Yoshioka A, Tonoki H, Tsukino R, Niikawa N (1991) Molecular study of the Prader-Willi syndrome: deletion, RFLP, and phenotype analyses of 50 patients. Am J Med Genet 41:54–63PubMedCrossRefGoogle Scholar
  31. Helleman J, Jansen M, Span P, van Staveren I, Massuger L, Meijer-van Gelder M, Sweep F, Ewing P, van der Burg M, Stoter G, Nooter K, Berns E (2006) Molecular profiling of platinum resistant ovarian cancer. Int J Cancer 118:1963–1971PubMedCrossRefGoogle Scholar
  32. Hoggart C, Parra E, Shriver M, Bonilla C, Kittles R, Clayton D, McKeigue P (2003) Control of confounding of genetic associations in stratified populations. Am J Hum Genet 72:1492–1504PubMedCrossRefGoogle Scholar
  33. Imesch P, Wallow I., Albert D (1997) The color of the human iris: a review of morphologic correlates and of some conditions that affect iridial pigmentation. Surv Ophthalmol 2(41Suppl):S117–S123CrossRefGoogle Scholar
  34. Lao O, de Gruijter J, van Dujin K, Navarro A, Kayser M (2007) Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms. Ann Hum Genet 71:354–369Google Scholar
  35. McKeigue P (1997) Mapping genes underlying ethnic differences in disease risk by linkage disequilibrium in recently admixed populations. Am J Hum Genet 60:188–196PubMedGoogle Scholar
  36. McKeigue P, Carpenter J, Para E, Shriver M (2000) Estimation of admixture and detection of linkage in admixed populations by a Bayesian approach: application to the African-American populations. Ann Hum Genet 64(pt2):171–186PubMedCrossRefGoogle Scholar
  37. Meinhold-Heerlein I, Bauerschlag D, Hilpert F, Dimitrov P, Sapinoso L, Orlowska-Volk M, Bauknecht T, Park T, Jonat W, Jacobsen A, Sehouli J, Luttges J, Drajewski M, Krajewski S, Reed J, Arnold N, Hampton G (2005) Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential. Oncogene 34:1053–1065CrossRefGoogle Scholar
  38. Molokhia M, Hoggart C, Patrick A, Shriver M, Parra E, Ye J, Silman A, McKeigue P (2003) Relation of risk of systemic lupus erythematosus to west African admixture in a Caribbean population. Hum Genet 112:301–308Google Scholar
  39. Oetting W, Gardner J, Fryer J, Ching A, Durham-Pierre D, King R, Brilliant M (1998) Mutations of the human P gene associated with Type II oculocutaneous albinism (OCA2). Hum Mutat 12:434PubMedCrossRefGoogle Scholar
  40. Ooi C, Moreira J, Dell’Angelica E, Poy G, Wassarman D, Bonifacino J (1997) Altered expression of a novel adaptin leads to defective pigment granule biogenesis in the Drosophila iris color mutant garnet. EMBO J 16:4508–4518PubMedCrossRefGoogle Scholar
  41. Ouellet V, Provencher D, Maugard C, Le Page C, Ren F, Lussier C, Novak J, Ge B, Hudson T, Tonin P, Mes-Masson A (2005) Discrimination between serous low malignant potential and invasive epithelial ovarian tumors using molecular profiling. Oncogene 24:4672–4687PubMedCrossRefGoogle Scholar
  42. Parra E, Kittles R, Shriver M (2004) Implications of correlations between skin color and genetic ancestry for biomedical research. Nat Genet 36:S54–S60PubMedCrossRefGoogle Scholar
  43. Parra E, Marcini A, Akey J, Martinson J, Batzer M, Cooper R, Forrester T, Allison D, Deka R, Ferrell R, Shriver M (1998) Estimating African American admixture proportions by use of population-specific alleles. Am J Hum Genet 63:1839–1851PubMedCrossRefGoogle Scholar
  44. Pfaff C, Parra E, Bonilla C, Hiester K, McKeigue P, Kamboh M, Hutchinson R, Ferrell R, Boerwinkle E, Shriver M (2001) Population structure in admixed populations: effect of admixture dynamics on the pattern of linkage disequilibrium. Am J Hum Genet 68:198–207PubMedCrossRefGoogle Scholar
  45. Posthuma D, Visscher P, Willemsen G, Zhu G, Martin N, Slagboom P, de Geus E, Boomsma D (2006) Replicated linkage for eye color on 15q using comparative ratings of sibling pairs. Behav Genet 36:12–17PubMedCrossRefGoogle Scholar
  46. Prota G, Hu D, Vincensi M, McCormick S, Napolitano A (1998) Characterization of melanins in human irides and cultured uveal melanocytes from eyes of different colors. Exp Eye Res 67:293–299PubMedCrossRefGoogle Scholar
  47. Purcell S, Cherny S, Sham P (2003) Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19:149–150PubMedCrossRefGoogle Scholar
  48. Puri N, Gardner J, Brilliant M (2000) Aberrant pH of melanosomes in pink-eyed dilution (p) mutant melanocytes. J Invest Dermatol 115:607–613PubMedCrossRefGoogle Scholar
  49. Ramaswamy S, Ross K, Lander E, Golub T (2003) A molecular signature of metastasis in primary solid tumors. Nature Gen 33:49–54CrossRefGoogle Scholar
  50. Reiner A, Ziv E, Lind D, Nievergelt C, Schork N, Cummings S, Phong A, Burchard E, Harris T, Psaty B, Kwok P (2005) Population structure, admixture, and aging-related phenotypes in African American adults: the cardiovascular health study. Am J Hum Genet 76:463–77PubMedCrossRefGoogle Scholar
  51. Rinchik E, Bultman S, Horsthemke B, Lee S, Strunk K, Spritz R, Avidano K, Jong M, Nicholls R (1993) A gene for the mouse pink-eyed dilution locus and for human type II oculocutaneous albinism. Nature 361:72–76PubMedCrossRefGoogle Scholar
  52. Robbins L, Nadeau J, Johnson K, Kelly M, Roselli-Rehfuss L, Baack E, Mountjoy K, Cone R (1993) Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 72:827–834PubMedCrossRefGoogle Scholar
  53. Rosenberg N, Mahajan S, Ramachandran S, Zhao C, Pritchard J, Feldman M (2005) Clines, clusters, and the effect of study design on the inference of human population structure. PLoS Genet 1:e70PubMedCrossRefGoogle Scholar
  54. Rosenberg N, Pritchard J, Weber J, Cann H, Kidd K, Zhivotovsky L, Feldman M (2002) Genetic structure of human populations. Science 298:2381–2385PubMedCrossRefGoogle Scholar
  55. Schneider S, Roessli D, Excoffier L (2000) Arlequin ver. 2.000: a software for population genetics data analysis. Genetics and Biometry Laboratory, University of Geneva, SwitzerlandGoogle Scholar
  56. Shriver M, Parra E, Dios S, Bonilla C, Norton H, Jovel C, Pfaff C, Jones C, Massac A, Cameron N, Baron A, Jackson T, Argyropoulos G, Jin L, Hoggart C, McKeigue P, Kittles R (2003) Skin pigmentation, biogeographical ancestry and admixture mapping. Hum Genet 112:388–399Google Scholar
  57. Shriver M, Mei R, Parra E, Sonpar V, Halder I, Tishkoff S, Schurr T, Zhadanov S, Osipova L, Brutsaert T, Friedlaender J, Jorde L, Watkins W, Bamshad M, Gutierrez G, Loi H, Matsuzaki H, Kittles R, Argyropoulos G, Fernandez J, Akey J, Jones K (2005) Large-scale SNP analysis reveals clustered and continuous patterns of human genetic variation. Hum Genom 2:81–89Google Scholar
  58. Shriver M, Kittles R (2004) Genetic ancestry and the search for personalized genetic histories. Nat Rev Genet 5:611–618PubMedCrossRefGoogle Scholar
  59. Smith R, Healy E, Siddiqui S, Flanagan N, Steijlen P, Rosdahl I, Jacques J, Rogers S, Turner R, Jackson I, Birch-Machin M, Rees J (1998) Melanocortin 1 receptor variants in an Irish population. J Invest Derm 111:119–122PubMedCrossRefGoogle Scholar
  60. Smith M, Patterson N, Lautenberger J, Truelove A, McDonald G, Waliszewska A, Kessing B, Malasky M, Scafe C, Le E, De Jager P, Mignault A, Yi Z, The G, Essex M, Sankale J, Moore J, Poku K, Phair J, Goedert J, Vlahov D, Williams S, Tishkoff S, Winkler C, De La Vega F, Woodage T, Sninsky J, Hafler D, Altshuler D, Gilvert D, O’Brien S, Reich D (2004) A high-density admixture map for disease gene discovery in African Americans. Am J Hum Genet 74:1001–1013PubMedCrossRefGoogle Scholar
  61. Stephens M, Smith N, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989PubMedCrossRefGoogle Scholar
  62. Stephens M, Donnelly P (2003) A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73:162–1169CrossRefGoogle Scholar
  63. Sturm R, Frudakis T (2004) Eye colour: portals into pigmentation genes and ancestry. Trends Genet 20:327–332PubMedCrossRefGoogle Scholar
  64. Sturm R, Teasdale R, Box N (2001) Human pigmentation genes: identification, structure and consequences of polymorphis variation. Gene 277:49–62PubMedCrossRefGoogle Scholar
  65. Terwilliger J, Goring H (2000) Gene mapping in the 20th and 21st centuries: statistical methods, data analysis, and experimental design. Hum Biol 72:63–132PubMedGoogle Scholar
  66. Voight B, Kudaravalli S, Wen X, Pritchard J (2006) A map of recent positive selection in the human genome. PLoS Biol 4:e72PubMedCrossRefGoogle Scholar
  67. Yang N, Li H, Criswell L, Gregersen P, Alarcon-Riquelme M, Kittles R, Shigata R, Silva G, Patel P, Belmont J, Seldin M (2005) Examination of ancestry and ethnic affiliation using highly informative diallelic DNA markers: application to diverse and admixed populations and implications for clinical epidemiology and forensic medicine. Hum Genet 118:382–392PubMedCrossRefGoogle Scholar
  68. Zhu G, Evans D, Duffy D, Montgomery G, Medland S, Gillespie N, Ewen K, Jewell M, Liew Y, Hayward N, Sturm R, Trent J, Martin N (2004) A genome scan for eye color in 502 twin families: most variation is due to a QTL on chromosome 15q. Twin Res 7:197–210PubMedCrossRefGoogle Scholar
  69. Zhu X, Luke A, Cooper R, Quertermous T, Hanis C, Mosley T, Gu C, Tang H, Rao D, Risch N, Welder A (2005) Admixture mapping for hypertension loci with genome-scan markers. Nat Genet 37:177–181PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Tony Frudakis
    • 1
    Email author
  • Timothy Terravainen
    • 2
  • Matthew Thomas
    • 1
  1. 1.DNAPrint Genomics, IncSarasotaUSA
  2. 2.Department of StatisticsColumbia UniversityNew YorkUSA

Personalised recommendations