Genetic Epidemiology, Translational Neurogenomics, Psychiatric 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
10417291
TITLE
A major quantitative-trait locus for mole density is linked to the familial melanoma gene CDKN2A: a maximum-likelihood combined linkage and association analysis in twins and their sibs.
ABSTRACT
Important risk factors for melanoma are densely clustered melanocytic nevi (common moles) and mutations in the p16 (CDKN2A) gene. Nevi may be subclassified as raised or flat. In our sample, raised nevi were 27% of the total, and the two kinds had a correlation of.33. Correlations for total-nevus count (TNC) in 153 MZ and 199 DZ twin pairs were.94 and.60, respectively, which are compatible with a very-high degree of genetic determination. We hypothesized that some of the genetic variance might be due to variation in the p16 gene. Analysis of linkage to a highly polymorphic marker (D9S942), located close to p16, detected quantitative-trait-loci (QTL) effects accounting for 27% of variance in TNC, rising to 33% if flat but not raised moles were considered. Total heritability was higher for raised (.69) than for flat (.42) moles, but QTL linkage was 0 for raised moles, whereas it accounted for 80% of the heritability of flat moles; additionally, family environment accounted for only 15% of variance in raised versus 46% in flat moles. These findings suggest that raised and flat nevi have very different etiologies. Longer alleles at D9S942 were associated with higher flat-mole counts, and a novel modification to a within-sibship association test showed that this association is genuine and not due to population stratification, although it accounts for only 1% of total variance. Since germline mutations in the exons of CDKN2A are rare, it is likely that variants in the noncoding regions of this gene, or in another gene nearby, are responsible for this major determinant of moliness and, hence, of melanoma risk.
DATE PUBLISHED
1999 Aug
HISTORY
PUBSTATUS PUBSTATUSDATE
pubmed 1999/07/27 10:00
medline 2000/03/21 09:00
entrez 1999/07/27 10:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Zhu G Zhu G G Queensland Institute of Medical Research and Joint Genetics Program, University of Queensland, Brisbane, Australia.
Duffy DL Duffy D L DL
Eldridge A Eldridge A A
Grace M Grace M M
Mayne C Mayne C C
O'Gorman L O'Gorman L L
Aitken JF Aitken J F JF
Neale MC Neale M C MC
Hayward NK Hayward N K NK
Green AC Green A C AC
Martin NG Martin N G NG
INVESTIGATORS
JOURNAL
VOLUME: 65
ISSUE: 2
TITLE: American journal of human genetics
ISOABBREVIATION: Am. J. Hum. Genet.
YEAR: 1999
MONTH: Aug
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, Non-U.S. Gov't
Twin Study
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Child
Diseases in Twins genetics
Female genetics
Genes, p16 genetics
Genetic Heterogeneity genetics
Genetic Linkage genetics
Genetic Predisposition to Disease genetics
Genetic Variation genetics
Humans genetics
Likelihood Functions genetics
Linkage Disequilibrium genetics
Male genetics
Matched-Pair Analysis genetics
Melanoma genetics
Molecular Sequence Data genetics
Nevus, Pigmented pathology
Nuclear Family pathology
Polymorphism, Genetic genetics
Quantitative Trait, Heritable genetics
Regression Analysis genetics
Skin Neoplasms pathology
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's
OTHERID SOURCE
PMC1377947 NLM
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