Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene.
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.
Kayser
Manfred
M
Department of Forensic Molecular Biology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands. m.kayser@erasmusmc.nl
Liu
Fan
F
Janssens
A Cecile J W
AC
Rivadeneira
Fernando
F
Lao
Oscar
O
van Duijn
Kate
K
Vermeulen
Mark
M
Arp
Pascal
P
Jhamai
Mila M
MM
van Ijcken
Wilfred F J
WF
den Dunnen
Johan T
JT
Heath
Simon
S
Zelenika
Diana
D
Despriet
Dominiek D G
DD
Klaver
Caroline C W
CC
Vingerling
Johannes R
JR
de Jong
Paulus T V M
PT
Hofman
Albert
A
Aulchenko
Yurii S
YS
Uitterlinden
Andre G
AG
Oostra
Ben A
BA
van Duijn
Cornelia M
CM
D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D005127:Eye Color / Q000235:genetics*; D005786:Gene Expression Regulation; D023281:Genomics / Q000379:methods; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D026901:Membrane Transport Proteins; D046228:Microarray Analysis; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044767:Ubiquitin-Protein Ligases; D044465:White People / Q000235:genetics
D020662:Guanine Nucleotide Exchange Factors; D026901:Membrane Transport Proteins; C489600:OCA2 protein, human; C118566:HERC2 protein, human; D044767:Ubiquitin-Protein Ligases