Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3

Abstract

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.

Figure 1

Association results for SNPs directly genotyped in all Australian samples. SNPs with P-values exceeding genome-wide significance (P < 5 × 10⁻⁸) are shown in black, while SNPs with 5 × 10⁻⁸ < P < 1 × 10⁻⁶ are shown in blue. The y-axis is truncated at 1 × 10⁻⁹, however, some SNPs from previously identified loci exceed this threshold (specifically at ~88 Mb on chromosome 16 near MC1R and at the ASIP locus 33 Mb on chromosome 20. The genome-wide significant signal on chromosome 9 is in the vicinity of the MTAP/CDKN2A region.

Figure 2

Discovery sample association results at two novel melanoma susceptibility loci on chromosome 1 for both SNPs directly genotyped in all Australian samples and imputed SNPs. Genotyped SNPs are indicated by solid triangles and imputed SNPs by hollow circles. The top ranked SNP at each locus is shown as a solid purple diamond (this SNP is an imputed SNP at both loci). Imputation p-values for all SNPs are plotted. Note imputed and genotyped p-values for genotyped SNPs differ slightly because for the imputed result, analysis is based on dosage scores whereas with genotyped SNPs hard genotype calls are used. Association results shown are for (A) the chromosome 1 locus near 149 Mb, and (B) SNPs in the vicinity of the PARP1 association signal. The color scheme indicates linkage disequilibrium between the most strongly-associated SNPs for the 149 Mb and PARP1 region (shown in purple, rs267735 and rs2695238, respectively) and other genotyped SNPs in the two regions.

Figure 2

Discovery sample association results at two novel melanoma susceptibility loci on chromosome 1 for both SNPs directly genotyped in all Australian samples and imputed SNPs. Genotyped SNPs are indicated by solid triangles and imputed SNPs by hollow circles. The top ranked SNP at each locus is shown as a solid purple diamond (this SNP is an imputed SNP at both loci). Imputation p-values for all SNPs are plotted. Note imputed and genotyped p-values for genotyped SNPs differ slightly because for the imputed result, analysis is based on dosage scores whereas with genotyped SNPs hard genotype calls are used. Association results shown are for (A) the chromosome 1 locus near 149 Mb, and (B) SNPs in the vicinity of the PARP1 association signal. The color scheme indicates linkage disequilibrium between the most strongly-associated SNPs for the 149 Mb and PARP1 region (shown in purple, rs267735 and rs2695238, respectively) and other genotyped SNPs in the two regions.