Genome-wide association study identifies variation at 6q25.1 associated with survival in multiple myeloma

Abstract

Survival following a diagnosis of multiple myeloma (MM) varies between patients and some of these differences may be a consequence of inherited genetic variation. In this study, to identify genetic markers associated with MM overall survival (MM-OS), we conduct a meta-analysis of four patient series of European ancestry, totalling 3,256 patients with 1,200 MM-associated deaths. Each series is genotyped for ∼600,000 single nucleotide polymorphisms across the genome; genotypes for six million common variants are imputed using 1000 Genomes Project and UK10K as the reference. The association between genotype and OS is assessed by Cox proportional hazards model adjusting for age, sex, International staging system and treatment. We identify a locus at 6q25.1 marked by rs12374648 associated with MM-OS (hazard ratio=1.34, 95% confidence interval=1.22-1.48, P=4.69 × 10(-9)). Our findings have potential clinical implications since they demonstrate that inherited genotypes can provide prognostic information in addition to conventional tumor acquired prognostic factors.

Figure 1. Association plot for combined analyses for MM-OS.

The P-values of the association between each SNP and myeloma survival were obtained by Cox regression analyses with adjustment and then combined. The y axis shows the −log₁₀ P-values of each SNP analysed, and the x axis shows their respective chromosome position. The red horizontal line corresponds to P=5.0 × 10⁻⁸. All statistical tests were two-sided.

Figure 2. Regional plot of association results and recombination rates for the rs12374648 (6q25.1) MM-OS risk locus.

Plots show association results of both genotyped (triangles) and imputed (circles) SNPs in the GWAS samples and recombination rates. −log₁₀ P-values (y axes) of the SNPs are shown according to their chromosomal positions (x axes). The top genotyped SNP in each combined analysis is shown as a large diamond and is labelled by its rsID. The colour intensity of each symbol reflects the extent of LD with the top genotyped SNP, white (r²=0) through to dark red (r²=1.0). Genetic recombination rates, estimated using HapMap samples from Utah residents of western and northern European ancestry (CEU), are shown with a light blue line. Physical positions are based on NCBI build 37 of the human genome. Also shown are the relative positions of genes and transcripts mapping to the region of association. Genes have been redrawn to show their relative positions; therefore, maps are not to physical scale. Below each plot is a diagram of the exons and introns of the genes of interest.

Figure 3. Kaplan–Meier curves for MM-OS at 6q25.1 (rs12374648).

Survival curves for the AA homozygotes are shown as a solid line. The red line depicts the survival curve for the AG heterozygotes, and the dashed line depicts the survival curve for the rare homozygotes GG. Vertical ticks indicate censored data points.