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
| Autor: | Carol Mayne, Nicholas G. Martin, David L. Duffy, A. Eldridge, Adèle C. Green, Joanne F. Aitken, Louise O'Gorman, Nicholas K. Hayward, M. Grace, Gu Zhu, Michael C. Neale |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Male
Linkage disequilibrium Skin Neoplasms Genetic Linkage Matched-Pair Analysis Molecular Sequence Data Twins Locus (genetics) p16 Biology Quantitative trait locus Linkage Disequilibrium Nuclear Family 03 medical and health sciences CDKN2A Genetic Heterogeneity 0302 clinical medicine Quantitative Trait Heritable Genetic variation Genetics Diseases in Twins Humans Genetics(clinical) Genetic Predisposition to Disease Child Melanoma Genetics (clinical) 030304 developmental biology Genetic association 0303 health sciences Likelihood Functions Nevus Pigmented Polymorphism Genetic Genetic heterogeneity Linkage Genes p16 Genetic Variation Heritability Melanocytic nevi 030220 oncology & carcinogenesis Regression Analysis Female Research Article |
| Zdroj: | American journal of human genetics. 65(2) |
| ISSN: | 0002-9297 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|