A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci

Abstract

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.

Figure 1. Study design of multi-stage GWAS of bladder cancer

See Online Methods and Supplementary Table 1 for details of study designs and sample sizes. *The tag SNP, rs1495741 located 3′ of NAT2 was genotyped in subjects in stage II and III studies as well as on the Illumina bead chips used in stage I. **Includes 338 additional cases from NBCS that were added to the final combined analyses.

Figure 2. Association results, recombination and linkage disequilibrium plots for four regions on chromosomes 22q13.1, 19q12, 2q37.1 and 8p22

Results of stage I (green circles), combined stages II and III (blue diamonds) and combined data from the three stages (red diamonds) with P-values for log-additive association results with recombination rates (cm/Mb) based on HapMap phase II data. Pairwise r² values based on control populations are displayed at the bottom for all SNPs included in the GWAS analysis. Panel A depicts chromosome 22q13.1 region (37,617,065 to 37,743,614). Panel B depicts the region of chromosome 19q12 (34,922,089 to 35,080,325). Panel C depicts the region of 2q37.1 (234,131,582 to 234,286,564). Panel D depicts the region of 8p22 (18,216,291 to 18,406,519). Genomic coordinates are based on NCBI Human Genome Build 36.3.