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

Important risk factors for melanoma are densely clustered melanocytic nevi (common moles) and mutations in the p16 (CDKN2A) gene. Nevi may be subclass ified 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 co unt (TNC) in 153 MZ and 199 DZ twin pairs were .94 and .60, respectively, w hich are compatible with a very-high degree of genetic determination. We hy pothesized that some of the genetic variance might be due to variation in t he p16 gene. Analysis of linkage to a highly polymorphic marker (D9S942), l ocated close to p16, detected quantitative-trait-loci (QTL) effects account ing 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 fl at (.42) moles, but QTL linkage was 0 for raised moles, whereas it accounte d for 80% of the heritability of flat moles; additionally, family environme nt accounted for only 15% of variance in raised versus 46% in flat moles. T hese findings suggest that raised and flat nevi have very different etiolog ies. 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, altho ugh 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 r egions of this gene, or in another gene nearby, are responsible for this ma jor determinant of moliness and, hence, of melanoma risk.