A recent genome-wide association study (GWAS) of bladder cancer identified a single nucleotide polymorphism (SNP), rs11892031, within the UGT1A gene cluster on chromosome 2q37.1, as a novel risk factor. The UGT1A locus encodes nine UGT proteins, which belong to the phase II cellular detoxification system. UGTs are functionally important for the detoxification of aromatic amines, which are found in industrial chemicals and tobacco smoke and are known risk factors for bladder cancer. The UGT-encoding genes have exons 2 to 5 in common but have different first exons, which define the enzymatic activity and substrate specificity of the gene products.
Methods and results
We sequenced all nine highly similar alternative first exons for the UGT-encoding genes of up to 2,000 individuals. We identified 26 known nonsynonymous and 17 known synonymous coding variants but no novel variants. Imputation based on the GWAS dataset, a combined reference panel of HapMap 3 and the 1000 Genomes Project, and a subset of GWAS samples genotyped for all of the identified coding variants generated data for 1,170 SNPs within the whole UGT1A region. Of these markers, the strongest association was detected for an uncommon protective genetic variant that explained the original GWAS signal (odds ratio (OR) = 0.55, 95% confidence interval (CI) = 0.44 to 0.69, P = 3.3 × 10–7 in 4,035 cases and 5, 284 controls; D′ = 0.96, r2 = 0.23 with rs11892031). No residual association in this region was detected after adjustment for this SNP. A typical genetic variant identified by GWAS for a common disease is expected to be a common allele (>10% minor allele frequency) that increases the disease risk. We show that the novel associated variant is an uncommon protective allele (1.14% in cases and 2.5% in controls). Interestingly, the risk allele (G) is conserved in 33 species, whereas the protective allele (T) is a human-specific variant. Even though this SNP is a synonymous coding variant, we show its association with quantitative mRNA expression of a specific functional splicing form of UGT1A6, probably through an exonic splicing enhancer.
This study exemplifies that uncommon protective genetic variants are unusual suspects that may play important but underestimated functional roles in complex traits.