Common variants on 1p36 and 1q42 are associated with cutaneous basal cell carcinoma but not with melanoma or pigmentation traits

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Abstract

To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide SNP association study of 930 Icelanders with BCC and 33,117 controls. After analyzing 304,083 SNPs, we observed signals from loci at 1p36 and 1q42, and replicated these associations in additional sample sets from Iceland and Eastern Europe. Overall, the most significant signals were from rs7538876 on 1p36 (OR = 1.28, P = 4.4 × 10−12) and rs801114 on 1q42 (OR = 1.28, P = 5.9 × 10−12). The 1p36 locus contains the candidate genes PADI4, PADI6, RCC2 and ARHGEF10L, and the gene nearest to the 1q42 locus is the ras-homolog RHOU. Neither locus was associated with fair pigmentation traits that are known risk factors for BCC, and no risk was observed for melanoma. Approximately 1.6% of individuals of European ancestry are homozygous for both variants, and their estimated risk of BCC is 2.68 times that of noncarriers.

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Figure 1: Association of chromosome 1p36 region with BCC.
Figure 2: Allele rs7538876[A] is associated with increased expression of RCC2 in adipose tissue–derived RNA.
Figure 3: Multigenic risk model for BCC based on susceptibility variants at 1p36, 1q42, ASIP, TYR and MC1R loci.

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Acknowledgements

We thank G.H. Olafsdottir for assistance in the ascertainment of affected individuals.

Author information

The study was designed and results were interpreted by S.N.S., D.F.G., P.S., A.K., J.H.O., U.T. and K.S. Statistical analysis was carried out by D.F.G., P.S., G.T., A.H., F.G. and A.K. Subject ascertainment and recruitment was organized and carried out by S.N.S., R.K., B.S., K.R.B., K.T., R.R., D.S., P.R., E.G., K. Koppova, V.M., R.B.-E., V.S., P.J., M.G., F.J.C., P.T., Y.G., K. Kristjansson, G.B., S.G.S., E.N., J.I.M., J.H., J.H.O. and U.T. Biological material collection and handling was supervised by S.N.S., D.S., P.R., E.G., K. Koppova, V.M., R.B.-E., V.S., P.J., M.G., F.J.C., P.T., Y.G., T.R., M.J., J.G., S.T., J.S., K. Kristjansson, S.G.S., E.N., J.I.M., J.H. and U.T. Genotyping was supervised by S.N.S., T.R., M.J., J.G., S.T., M.M. and U.T. Expression analysis was carried out by J.T.B., G.T., A.S., T.T., A.J. and T.B. Bioinformatic analysis was carried out by S.A.G. and G.F.J. Authors S.N.S., D.F.G., P.S., U.T. and K.S. drafted the manuscript. All authors contributed to the final version of the paper. Principal collaborators for the case-control population samples were J.H.O. (Iceland), R.K. (Eastern Europe), J.I.M. and E.N. (Spain), and J.H. (Sweden).

Correspondence to Unnur Thorsteinsdottir or Kari Stefansson.

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Competing interests

Authors whose affiliations are listed as deCODE Genetics are shareholders and/or employees of deCODE Genetics, a biotechnology company. deCODE Genetics intends to incorporate the variants described in this paper into its genetic-testing services.

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