Pathway analysis of genome-wide association studies (GWAS) offer a
unique opportunity to collectively evaluate genetic variants with
effects that are too small to be detected individually. We applied a
pathway analysis to a bladder cancer GWAS containing data from 3,532
cases and 5,120 controls of European background (n = 5 studies).
Thirteen hundred and ninety-nine pathways were drawn from five publicly
available resources (Biocarta, Kegg, NCI-PID, HumanCyc, and Reactome),
and we constructed 22 additional candidate pathways previously
hypothesized to be related to bladder cancer. In total, 1421 pathways,
5647 genes and similar to 90,000 SNPs were included in our study.
Logistic regression model adjusting for age, sex, study, DNA source, and
smoking status was used to assess the marginal trend effect of SNPs on
bladder cancer risk. Two complementary pathway-based methods (gene-set
enrichment analysis [GSEA], and adapted rank-truncated product
[ARTP]) were used to assess the enrichment of association signals
within each pathway. Eighteen pathways were detected by either GSEA or
ARTP at P <= 0.01. To minimize false positives, we used the I-2
statistic to identify SNPs displaying heterogeneous effects across the
five studies. After removing these SNPs, seven pathways (’Aromatic amine
metabolism’ [P-GSEA = 0.0100, P-ARTP = 0.0020], ‘NAD biosynthesis’
[P-GSEA = 0.0018, P-ARTP = 0.0086], ‘NAD salvage’ [P-ARTP = 0.0068],
‘Clathrin derived vesicle budding’ [P-ARTP = 0.0018], ‘Lysosome
vesicle biogenesis’ [P-GSEA = 0.0023, P-ARTP < 0.00012], ‘Retrograde
neurotrophin signaling’ [P-GSEA = 0.00840], and ‘Mitotic
metaphase/anaphase transition’ [P-GSEA = 0.0040]) remained. These
pathways seem to belong to three fundamental cellular processes
(metabolic detoxification, mitosis, and clathrin-mediated vesicles).
Identification of the aromatic amine metabolism pathway provides support
for the ability of this approach to identify pathways with established
relevance to bladder carcinogenesis