Genome-wide association study identifies three new melanoma susceptibility loci

Abstract

We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 × 10(-9)), an SNP in MX2 (rs45430, P = 2.9 × 10(-9)) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10(-7) under a fixed-effects model and P = 1.2 × 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.

Figure 1

Manhattan plot of results of Cochran-Armitage (CA) trend test stratified by geographic region, with -log₁₀ p-values shown. The solid horizontal line indicates a p-value of 10⁻⁵. Markers within 50kb of a SNP associated with melanoma are marked in black for those identified in a previous GWA and replicated here and marked in red if first identified in the current study. The y-axis is truncated at p=10⁻¹⁵, although three SNPs in the MC1R region have stronger p-values, up to 2.7×10⁻²⁷, as signified by the box and arrow.

Figure 2

Stratified CA trend tests for the three replicated regions on chromosomes 2, 11 and 21. The log₁₀ p-values are from the CA trend test (stratified by geographical region) for genotyped and imputed SNPs, indicated on the left-hand vertical axis. SNPs genotyped for all samples are plotted as circles, SNPs imputed for all samples as crosses and SNPs genotyped for some samples and imputed for others (due to chip differences) as squares. The most significant genotyped SNP is colored purple (with its name above) and the degree of LD between that SNP and the others is indicated by color according to the key (red being the greatest degree of LD). The estimated recombination rate is given by the blue line and indicated on the right-hand vertical axis. The genes in the region and their positions are given underneath the graph. Plots produced using LocusZoom.

Figure 3

Forest plot of the per-allele OR for melanoma for SNPs in the 3 regions first identified in this study. Plots show the current evidence for effects by geography, in the genome-wide and replication samples, and by case type (family history, multiple primaries or early onset).