TY - JOUR
T1 - A genome-wide scan for naevus count
T2 - Linkage to CDKN2A and to other chromosome regions
AU - Zhu, Gu
AU - Montgomery, Grant W.
AU - James, Michael R.
AU - Trent, Jeff M.
AU - Hayward, Nicholas K.
AU - Martin, Nicholas G.
AU - Duffy, David L.
N1 - Funding Information:
Collection of phenotypes and DNA samples was supported by grants from the Queensland Cancer Fund (NGM, NKH), the Australian National Health and Medical Research Council (950998, 981339 and 241944; NGM), and the US National Cancer Institute (CA88363; NKH, NGM, DLD, GWM). The genome scans were supported by the Australian NHMRC’s Program in Medical Genomics (NHMRC 219178; NGM, GWM, DLD) and the Center for Inherited Disease Research (CIDR; Director, Dr Jerry Roberts) at The Johns Hopkins University (JMT, NGM). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University (Contract Number N01-HG-65403). We thank Ann Eldridge, Marlene Grace for phenotype collection, Megan Campbell and Anjali Henders for managing sample processing and preparation; and the twins, their siblings, and their parents for their cooperation.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2007/1
Y1 - 2007/1
N2 - High numbers of melanocytic naevi (moles), and mutations in the p16 gene (CDKN2A), are two strong risk factors for cutaneous malignant melanoma. We have previously reported linkage of mole count to the CDKN2A locus. Here, we report genome-wide scans for mole counts (differentiated into flat, raised and atypical subtypes) with a total of 796 microsatellite markers for 424 families with 1024 twins and siblings, plus genotypes for 690 parents. Inclusion of 221 pairs of MZ twins enabled separation of shared environmental and polygenic influences, so placing an upper limit to estimates of QTL variance. Maximum likelihood multipoint variance component methods were used to assess linkage of naevus count. Sex, age, body surface area, skin colour, hair colour, sunburn and facial freckles were included as covariates. Peak linkage of flat mole count was to regions on chromosomes 2, 9, 8 and 17 with lod scores 2.95, 2.95, 2.50 and 2.15, respectively. The support for linkage to the CDKN2A gene region (9p21) increased to 3.42 when additional fine mapping markers were added. For raised mole count, there was suggestive evidence of linkage in our sample to chromosome 16 (lod = 1.87), and for atypical mole count on chromosomes 1, 6 and X with lod scores of 2.20, 2.00 and 2.00, respectively. The multivariate linkage peaks generally match those from individual trait analyses, with the exception of a new peak on chromosome 4 (point-wise empirical P-value = 0.001). We replicate our earlier finding of linkage to CDKN2A and discovering linkage to several novel regions that may also influence risk of the development of malignant melanoma.
AB - High numbers of melanocytic naevi (moles), and mutations in the p16 gene (CDKN2A), are two strong risk factors for cutaneous malignant melanoma. We have previously reported linkage of mole count to the CDKN2A locus. Here, we report genome-wide scans for mole counts (differentiated into flat, raised and atypical subtypes) with a total of 796 microsatellite markers for 424 families with 1024 twins and siblings, plus genotypes for 690 parents. Inclusion of 221 pairs of MZ twins enabled separation of shared environmental and polygenic influences, so placing an upper limit to estimates of QTL variance. Maximum likelihood multipoint variance component methods were used to assess linkage of naevus count. Sex, age, body surface area, skin colour, hair colour, sunburn and facial freckles were included as covariates. Peak linkage of flat mole count was to regions on chromosomes 2, 9, 8 and 17 with lod scores 2.95, 2.95, 2.50 and 2.15, respectively. The support for linkage to the CDKN2A gene region (9p21) increased to 3.42 when additional fine mapping markers were added. For raised mole count, there was suggestive evidence of linkage in our sample to chromosome 16 (lod = 1.87), and for atypical mole count on chromosomes 1, 6 and X with lod scores of 2.20, 2.00 and 2.00, respectively. The multivariate linkage peaks generally match those from individual trait analyses, with the exception of a new peak on chromosome 4 (point-wise empirical P-value = 0.001). We replicate our earlier finding of linkage to CDKN2A and discovering linkage to several novel regions that may also influence risk of the development of malignant melanoma.
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U2 - 10.1038/sj.ejhg.5201729
DO - 10.1038/sj.ejhg.5201729
M3 - Article
C2 - 17063143
AN - SCOPUS:33845520278
SN - 1018-4813
VL - 15
SP - 94
EP - 102
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 1
ER -