title: Novel quantitative pigmentation phenotyping enhances genetic association, epistasis, and prediction of human eye colour.
abstract: Success of genetic association and the prediction of phenotypic traits from DNA are known to depend on the accuracy of phenotype characterization, amongst other parameters. To overcome limitations in the characterization of human iris pigmentation, we introduce a fully automated approach that specifies the areal proportions proposed to represent differing pigmentation types, such as pheomelanin, eumelanin, and non-pigmented areas within the iris. We demonstrate the utility of this approach using high-resolution digital eye imagery and genotype data from 12 selected SNPs from over 3000 European samples of seven populations that are part of the EUREYE study. In comparison to previous quantification approaches, (1) we achieved an overall improvement in eye colour phenotyping, which provides a better separation of manually defined eye colour categories. (2) Single nucleotide polymorphisms (SNPs) known to be involved in human eye colour variation showed stronger associations with our approach. (3) We found new and confirmed previously noted SNP-SNP interactions. (4) We increased SNP-based prediction accuracy of quantitative eye colour. Our findings exemplify that precise quantification using the perceived biological basis of pigmentation leads to enhanced genetic association and prediction of eye colour. We expect our approach to deliver new pigmentation genes when applied to genome-wide association testing.
authors.affiliation: Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.|Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.|Section of Evolutionary Biology, Department of Biology II, University of Munich LMU, Planegg-Martinsried, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wollstein
authors.affiliation: Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.|Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Walsh
authors.affiliation: Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.|Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.affiliation: Centre for Vision and Vascular Science, The Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Usha
authors.initials: U
authors.lastname: Chakravarthy
authors.affiliation: Department of Epidemiology and Biostatistics, National Institute for Health Development, Tallinn, Estonia.
authors.forename: Mati
authors.initials: M
authors.lastname: Rahu
authors.affiliation: Department of Ophthalmology, University of Bergen, School of Medicine, Bergen, Norway.
authors.forename: Johan H
authors.initials: JH
authors.lastname: Seland
authors.affiliation: Clinique Ophthalmologique, Universitaire De Creteil, Paris, France.
authors.forename: Gisèle
authors.initials: G
authors.lastname: Soubrane
authors.affiliation: Clinica Oculistica, Universita degli studi di Verona, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Tomazzoli
authors.affiliation: Department of Ophthalmology, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki, Greece.
authors.forename: Fotis
authors.initials: F
authors.lastname: Topouzis
authors.affiliation: Department of Ophthalmology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Vingerling
authors.affiliation: Dpto. Salud Publica Universidad Miguel Hernandez, Alicante, El Centro de Investigacion Biomedica en Red de Epidemiologıa y Salud Publica (CIBERESP), Elche, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Vioque
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Böhringer
authors.affiliation: Faculty of Epidemiology &Population Health, London School of Hygiene &Tropical Medicine, London, United Kingdom.
authors.forename: Astrid E
authors.initials: AE
authors.lastname: Fletcher
authors.affiliation: Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kayser
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D017920:Antiporters / Q000235:genetics / Q000378:metabolism; D003952:Diagnostic Imaging; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism; D004843:Epistasis, Genetic; D005060:Europe; D005127:Eye Color / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D007498:Iris / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D008543:Melanins / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010858:Pigmentation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D044767:Ubiquitin-Protein Ligases; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D044465:White People; D000099218:Interferon Regulatory Factor-4
chemical_list: D000951:Antigens, Neoplasm; D017920:Antiporters; D005136:Eye Proteins; D020662:Guanine Nucleotide Exchange Factors; D050835:Interferon Regulatory Factors; D008543:Melanins; D026901:Membrane Transport Proteins; D044767:Ubiquitin-Protein Ligases; D033921:Vesicular Transport Proteins; D000099218:Interferon Regulatory Factor-4; C102161:LYST protein, human; C470570:SLC24A4 protein, human; C510061:SLC45A2 protein, human; C018362:pheomelanin; C041877:eumelanin; C118566:HERC2 protein, human