Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
17236130
TITLE
A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation.
ABSTRACT
We have previously shown that a quantitative-trait locus linked to the OCA2 region of 15q accounts for 74% of variation in human eye color. We conducted additional genotyping to clarify the role of the OCA2 locus in the inheritance of eye color and other pigmentary traits associated with skin-cancer risk in white populations. Fifty-eight synonymous and nonsynonymous exonic single-nucleotide polymorphisms (SNPs) and tagging SNPs were typed in a collection of 3,839 adolescent twins, their siblings, and their parents. The highest association for blue/nonblue eye color was found with three OCA2 SNPs: rs7495174 T/C, rs6497268 G/T, and rs11855019 T/C (P values of 1.02x10(-61), 1.57x10(-96), and 4.45x10(-54), respectively) in intron 1. These three SNPs are in one major haplotype block, with TGT representing 78.4% of alleles. The TGT/TGT diplotype found in 62.2% of samples was the major genotype seen to modify eye color, with a frequency of 0.905 in blue or green compared with only 0.095 in brown eye color. This genotype was also at highest frequency in subjects with light brown hair and was more frequent in fair and medium skin types, consistent with the TGT haplotype acting as a recessive modifier of lighter pigmentary phenotypes. Homozygotes for rs11855019 C/C were predominantly without freckles and had lower mole counts. The minor population impact of the nonsynonymous coding-region polymorphisms Arg305Trp and Arg419Gln associated with nonblue eyes and the tight linkage of the major TGT haplotype within the intron 1 of OCA2 with blue eye color and lighter hair and skin tones suggest that differences within the 5' proximal regulatory control region of the OCA2 gene alter expression or messenger RNA-transcript levels and may be responsible for these associations.
DATE PUBLISHED
2007 Feb
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2006/09/05
accepted 2006/11/15
aheadofprint 2006/12/20
pubmed 2007/01/20 09:00
medline 2007/03/14 09:00
entrez 2007/01/20 09:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Duffy DL Duffy David L DL Queensland Institute of Medical Research, Brisbane, Australia.
Montgomery GW Montgomery Grant W GW
Chen W Chen Wei W
Zhao ZZ Zhao Zhen Zhen ZZ
Le L Le Lien L
James MR James Michael R MR
Hayward NK Hayward Nicholas K NK
Martin NG Martin Nicholas G NG
Sturm RA Sturm Richard A RA
INVESTIGATORS
JOURNAL
VOLUME: 80
ISSUE: 2
TITLE: American journal of human genetics
ISOABBREVIATION: Am. J. Hum. Genet.
YEAR: 2007
MONTH: Feb
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Print
ISSN: 0002-9297
ISSNTYPE: Print
MEDLINE JOURNAL
MEDLINETA: Am J Hum Genet
COUNTRY: United States
ISSNLINKING: 0002-9297
NLMUNIQUEID: 0370475
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
CA88363 NCI NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adolescent
Child
Chromosomes, Human, Pair 15 genetics
Eye Color genetics
Female genetics
Genotype genetics
Hair Color genetics
Haplotypes genetics
Humans genetics
Introns genetics
Male genetics
Melanosis genetics
Membrane Transport Proteins genetics
Nevus, Pigmented genetics
Polymorphism, Single Nucleotide genetics
Skin Pigmentation genetics
Twins genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Membrane Transport Proteins
0 OCA2 protein, human
OTHER ID's
OTHERID SOURCE
PMC1785344 NLM