Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry

Hum Mol Genet. 2016 Mar 15;25(6):1203-14. doi: 10.1093/hmg/ddv492. Epub 2016 Jan 4.

Abstract

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural

MeSH terms

  • Biomarkers, Tumor / genetics
  • Case-Control Studies
  • Chromosomes, Human, Pair 13*
  • Chromosomes, Human, Pair 20*
  • European Continental Ancestry Group / genetics*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study
  • Humans
  • Linkage Disequilibrium
  • Male
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Urinary Bladder Neoplasms / ethnology
  • Urinary Bladder Neoplasms / genetics*

Substances

  • Biomarkers, Tumor