Digital Quantification of Human Eye Color Highlights Genetic Association of Three New Loci

Previous studies have successfully identified genetic variants in several genes associated with human iris (eye) color; however, they all used simplified categorical trait information. Here, we quantified continuous eye color variation into hue and saturation values using high-resolution digital full-eye photographs and conducted a genome-wide association study on 5,951 Dutch Europeans from the Rotterdam Study. Three new regions, 1q42.3, 17q25.3, and 21q22.13, were highlighted meeting the criterion for genome-wide statistically significant association. The latter two loci were replicated in 2,261 individuals from the UK and in 1,282 from Australia. The LYST gene at 1q42.3 and the DSCR9 gene at 21q22.13 serve as promising functional candidates. A model for predicting quantitative eye colors explained over 50% of trait variance in the Rotterdam Study. Over all our data exemplify that fine phenotyping is a useful strategy for finding genes involved in human complex traits.

[1]  A. Brues.  Rethinking human pigmentation , 1975 .

[2]  N. Martin,et al.  KRAS variation and risk of endometriosis. , 2006, Molecular human reproduction.

[3]  IRWIN M. ARIAS.  Gilbert's syndrome. , 1968, British medical journal.

[4]  Y. S. Yu,et al.  Characteristic ocular findings in Asian children with Down syndrome , 2002, Eye.

[5]  J. Odeberg,et al.  UGT1A polymorphisms in a Swedish cohort and a human diversity panel, and the relation to bilirubin plasma levels in males and females , 2006, European Journal of Clinical Pharmacology.

[6]  Michael G. Anderson,et al.  Lyst mutation in mice recapitulates iris defects of human exfoliation syndrome. , 2009, Investigative ophthalmology & visual science.

[7]  P. Grimley,et al.  Chediak-Higashi syndrome. , 1969, Archives of pathology.

[8]  Thomas Lumley,et al.  Common variants at ten loci influence QT interval duration in the QTGEN Study , 2009, Nature Genetics.

[9]  F. Hu,et al.  A Genome-Wide Association Study Identifies Novel Alleles Associated with Hair Color and Skin Pigmentation , 2008, PLoS genetics.

[10]  A. Hofman,et al.  The Rotterdam Study: objectives and design update , 2007, European Journal of Epidemiology.

[11]  Nicholas G Martin,et al.  A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color. , 2008, American journal of human genetics.

[12]  Mats Larsson,et al.  Genetics of human iris colour and patterns , 2009, Pigment cell & melanoma research.

[13]  S. Alonso,et al.  A scan for signatures of positive selection in candidate loci for skin pigmentation in humans. , 2006, Molecular biology and evolution.

[14]  G. Abecasis,et al.  Merlin—rapid analysis of dense genetic maps using sparse gene flow trees , 2002, Nature Genetics.

[15]  J. Steibel,et al.  Characterization of a canine model of autosomal recessive retinitis pigmentosa due to a PDE6A mutation. , 2009, Investigative ophthalmology & visual science.

[16]  M. Shriver,et al.  The genetic architecture of normal variation in human pigmentation: an evolutionary perspective and model. , 2006, Human molecular genetics.

[17]  M. Holick,et al.  Factors that influence the cutaneous synthesis and dietary sources of vitamin D. , 2007, Archives of biochemistry and biophysics.

[18]  Yurii S. Aulchenko,et al.  BIOINFORMATICS APPLICATIONS NOTE doi:10.1093/bioinformatics/btm108 Genetics and population analysis GenABEL: an R library for genome-wide association analysis , 2022 .

[19]  Peter M Schneider,et al.  DNA-based prediction of human externally visible characteristics in forensics: motivations, scientific challenges, and ethical considerations. , 2009, Forensic science international. Genetics.

[20]  K. Nakashima,et al.  [The Rotterdam study]. , 2011, Nihon rinsho. Japanese journal of clinical medicine.

[21]  L. Madrigal,et al.  Human skin-color sexual dimorphism: a test of the sexual selection hypothesis. , 2007, American journal of physical anthropology.

[22]  Johan T den Dunnen,et al.  Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene. , 2008, American journal of human genetics.

[23]  M. Hattori,et al.  Identification of two novel primate-specific genes in DSCR. , 2002, DNA research : an international journal for rapid publication of reports on genes and genomes.

[24]  A. Uitterlinden,et al.  A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: the Treat-OA consortium , 2009, Journal of Medical Genetics.

[25]  R B Saenz,et al.  Primary care of infants and young children with Down syndrome. , 1999, American family physician.

[26]  H. Akaike.  A new look at the statistical model identification , 1974 .

[27]  Yurii S. Aulchenko,et al.  A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation , 2009, Human molecular genetics.

[28]  B. Maher.  Personal genomes: The case of the missing heritability , 2008, Nature.

[29]  Snæbjörn Pálsson,et al.  Two newly identified genetic determinants of pigmentation in Europeans , 2008, Nature Genetics.

[30]  Monique M. B. Breteler,et al.  The Rotterdam Study: 2016 objectives and design update , 2015, European Journal of Epidemiology.

[31]  Hans Eiberg,et al.  Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression , 2008, Human Genetics.

[32]  A. Hofman,et al.  Determinants of disease and disability in the elderly: The Rotterdam elderly study , 1991, European Journal of Epidemiology.

[33]  A. Cecile J.W. Janssens,et al.  Eye color and the prediction of complex phenotypes from genotypes , 2009, Current Biology.

[34]  Manfred Kayser,et al.  IrisPlex: a sensitive DNA tool for accurate prediction of blue and brown eye colour in the absence of ancestry information. , 2011, Forensic science international. Genetics.

[35]  G. Abecasis,et al.  Genotype imputation. , 2009, Annual review of genomics and human genetics.

[36]  P. Challa.  Genetics of pseudoexfoliation syndrome , 2009, Current opinion in ophthalmology.

[37]  David Patterson,et al.  Molecular genetic analysis of Down syndrome , 2009, Human Genetics.

[38]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[39]  C. Strassburg.  Pharmacogenetics of Gilbert's syndrome. , 2008, Pharmacogenomics.

[40]  J. Trent,et al.  A genome-wide scan for naevus count: linkage to CDKN2A and to other chromosome regions , 2007, European Journal of Human Genetics.

[41]  Mark D. Shriver,et al.  The 8818G allele of the agouti signaling protein (ASIP) gene is ancestral and is associated with darker skin color in African Americans , 2005, Human Genetics.

[42]  B. Burchell,et al.  Molecular genetic basis of Gilbert’s syndrome , 1999, Journal of gastroenterology and hepatology.

[43]  E. Parra,et al.  Human pigmentation variation: evolution, genetic basis, and implications for public health. , 2007, American journal of physical anthropology.

[44]  Wei Chen,et al.  A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation. , 2007, American journal of human genetics.

[45]  B. Gutiérrez-Gil,et al.  Genetic effects on coat colour in cattle: dilution of eumelanin and phaeomelanin pigments in an F2-Backcross Charolais × Holstein population , 2007, BMC Genetics.

[46]  T. Spector,et al.  Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi , 2009, Nature Genetics.

[47]  N. Pedersen,et al.  Importance of genetic effects for characteristics of the human iris. , 2003, Twin research : the official journal of the International Society for Twin Studies.

[48]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[49]  Snæbjörn Pálsson,et al.  Genetic determinants of hair, eye and skin pigmentation in Europeans , 2007, Nature Genetics.