Cited by 261melanin and skin pigmentationGenetic Associations and EpidemiologyForensic and Genetic Research

Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene

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Kayser, Manfred, Liu, Fan, Janssens, A. Cecile J.W., Rivadeneira, Fernando, Lao, Oscar, van Duijn, Kate, Vermeulen, Mark, Arp, Pascal +14 more·2008·The American Journal of Human Genetics

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.

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Crossref · 10.1016/j.ajhg.2007.10.003

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  • The eye color locus was later refined to a small region 50 kb upstream of OCA2 in an intron of the HERC2 gene.

    “This eye color locus was later refined to a small region 50 kb upstream of OCA2 in an intron of the HERC2 gene [7], [8], [10].”
  • OCA2 has been implicated in iris, skin, and hair pigmentation in humans.

    “In humans, it has been implicated in iris, skin, and hair pigmentation (Duffy et al. 2007; Sturm et al. 2008; Kayser et al. 2008; Sulem et al. 2007).”

    From A global view of the OCA2-HERC2 region and pigmentation (2012) · cites this paper as Kayser et al. 2008

  • Two other SNPs, rs916977 and rs1667394, have previously been associated with blue eyes.

    “Two other SNPs, rs916977 and rs1667394, have previously been associated with blue eyes (Kayser et al. 2008; Sulem et al. 2007).”

    From A global view of the OCA2-HERC2 region and pigmentation (2012) · cites this paper as Kayser et al. 2008

  • Several sites in and around OCA2 have been reported to be the functional variant or tightly linked to the functional variant leading to blue eyes, including a three-SNP haplotype (rs4778138, rs4778241, rs7495174) and four individual SNPs, rs1129038, rs12913832, rs916977, and rs1667394.

    “Several sites in and around OCA2 have been reported to be the functional variant or to be tightly linked to the functional variant leading to blue eyes. These sites include a three-SNP haplotype (rs4778138, rs4778241, rs7495174) and four individual SNPs, rs1129038, rs12913832, rs916977, and rs1667394 (Duffy et al. 2007; Sturm et al. 2008; Kayser et al. 2008; Sulem et al. 2007; Mengel-From et al. 2”

    From A global view of the OCA2-HERC2 region and pigmentation (2012) · cites this paper as Kayser et al. 2008

  • The TG allele of BEH2 has a much more restricted global distribution compared to the ACA allele of BEH1 and the CA allele of BEH3, the other two haplotypes published as associated with blue eyes.

    “We have shown that the TG allele of BEH2 has a much more restricted global distribution compared to the ACA allele of BEH1 and the CA allele of BEH3, the other two haplotypes published as associated with blue eyes”

    From A global view of the OCA2-HERC2 region and pigmentation (2012) · cites this paper as Kayser et al. 2008

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Authors
Kayser, M., Liu, F., Janssens, A. C. J. W., Rivadeneira, F., Lao, O., van Duijn, K., Vermeulen, M., Arp, P., Jhamai, M. M., van IJcken, W. F. J., den Dunnen, J. T., Heath, S., Zelenika, D., Despriet, D. D. G., Klaver, C. C. W., Vingerling, J. R., de Jong, P. T. V. M., Hofman, A., Aulchenko, Y. S., Uitterlinden, A. G., Oostra, B. A., & van Duijn, C. M.
Affiliations
  • Erasmus MC (NL)
  • Netherlands Forensic Institute (NL)
Corresponding author
Kayser, Manfred
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2008-02
Volume
82
Issue
2
Pages
411-423
ISSN
0002-9297 (ISSN-L)
OpenAlex
W2069491279
Cited by
260
References
49
Citations by year
2026: 4 · 2025: 4 · 2024: 15 · 2023: 11 · 2022: 10 · 2021: 14 · 2020: 14 · 2019: 9 · 2018: 12 · 2017: 13 · 2016: 12 · 2015: 14 · 2014: 12 · 2013: 22 · 2012: 16
FWCI
11.37
Type
journal article
Language
en
Open access
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (acceptedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • Pure Amsterdam UMC (submittedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion)
Funders
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (911-03-012, 175.010.200, 175.010.2005.011, 912-03-014)
  • Erasmus Universitair Medisch Centrum Rotterdam
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
Keywords
iris color, HERC2, OCA2, eye color genetics, single nucleotide polymorphisms, allele frequency clines, forensic identification, Mendelian segregation
MeSH terms
Chromosome Mapping, Chromosomes, Human, Pair 15, Eye Color, Gene Expression Regulation, Humans, Netherlands, Polymorphism, Single Nucleotide, Guanine Nucleotide Exchange Factors, Genomics, Membrane Transport Proteins, White People, Ubiquitin-Protein Ligases, Microarray Analysis

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