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• Articles by Manfred Kayser
• Articles by Cornelia M. van Duijn

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Three Genome-wide Association Studies and a Linkage Analysis Identify HERC2 as a Human Iris Color Gene

Manfred Kayser^1, ,  , Fan Liu², A. Cecile J.W. Janssens³, Fernando Rivadeneira^4, 5, Oscar Lao¹, Kate van Duijn¹, Mark Vermeulen^1, 8, Pascal Arp⁴, Mila M. Jhamai⁴, Wilfred F.J. van IJcken⁶, Johan T. den Dunnen⁹, Simon Heath¹⁰, Diana Zelenika¹⁰, Dominiek D.G. Despriet^5, 7, Caroline C.W. Klaver^5, 7, Johannes R. Vingerling^5, 7, Paulus T.V.M. de Jong^5, 11, 12, Albert Hofman⁵, Yurii S. Aulchenko², Andre G. Uitterlinden^4, 5, Ben A. Oostra² and Cornelia M. van Duijn²

¹ Department of Forensic Molecular Biology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
² Genetic Epidemiology Unit of the Departments of Epidemiology & Biostatistics and Clinical Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
³ Department of Public Health, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
⁴ Genetic Laboratory of the Department of Internal Medicine, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
⁵ Department of Epidemiology & Biostatistics, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
⁶ Erasmus Center for Biomics, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
⁷ Department of Ophthalmology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
⁸ Department of Biology, Netherlands Forensic Institute, 2490 AA Den Haag, The Netherlands
⁹ Leiden Genome Technology Center, Department of Human and Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
¹⁰ Centre National de Genotypage, 91057 Evry Cedex, France
¹¹ Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands
¹² Department of Ophthalmology, Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, The Netherlands

Corresponding author

Abstract

Human iris color was one of the first traits for which Mendelian segregation was established. To date, the genetics of iris color is still not fully understood and is of interest, particularly in view of forensic applications. In three independent genome-wide association (GWA) studies of a total of 1406 persons and a genome-wide linkage study of 1292 relatives, all from the Netherlands, we found that the 15q13.1 region is the predominant region involved in human iris color. There were no other regions showing consistent genome-wide evidence for association and linkage to iris color. Single nucleotide polymorphisms (SNPs) in the HERC2 gene and, to a lesser extent, in the neighboring OCA2 gene were independently associated to iris color variation. OCA2 has been implicated in iris color previously. A replication study within two populations confirmed that the HERC2 gene is a new and significant determinant of human iris color variation, in addition to OCA2. Furthermore, HERC2 rs916977 showed a clinal allele distribution across 23 European populations, which was significantly correlated to iris color variation. We suggest that genetic variants regulating expression of the OCA2 gene exist in the HERC2 gene or, alternatively, within the 11.7 kb of sequence between OCA2 and HERC2, and that most iris color variation in Europeans is explained by those two genes. Testing markers in the HERC2-OCA2 region may be useful in forensic applications to predict eye color phenotypes of unknown persons of European genetic origin.