Genome-wide association study identifies multiple loci associated with bladder cancer risk

Abstract

Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10(-5) was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10(-9)) and rs907611 on 11p15.5 (P = 4.11 × 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 × 10(-7)); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.

Figure 1.

See Supplementary Material, Table S1 for details of study designs and sample sizes. The New England Bladder Cancer Study (NEBCS) represents a single study comprises Maine (ME) and Vermont (VT) components genotyped in NCI-GWAS1, and the New Hampshire (NH) component genotyped in NCI-GWAS2.

Figure 2.

(A–D) The −log₁₀(P-value) (Y-axis) for NCI-GWAS1 and NCI-GWAS2 genotyped SNPs (blue) and imputed SNPs (gray) was plotted on the genomic coordinates (X-axis; NCBI genome build 37). The combined data for NCI-GWAS1, NCI-GWAS2, TXBCS-GWAS and TXBCS-TaqMan for four novel regions rs10936599 (3q16.2), rs907611 (11p15.5), rs6104690 (20p12.2) and rs4510656 (6p22.3) are shown in red.