Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer

Abstract

We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 x 10(-8); multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12-1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.

Figure 1. Manhattan plot of the P values in the pancreatic cancer GWAS

The association with pancreatic cancer is shown for the entire GWAS (12 cohort studies, and the Mayo case-control study, see Online Methods) (A), and the results of the GWAS including only the 12 cohorts studies (B). Association was assessed using unconditional logistic regression adjusted for study, arm, age, sex, ancestry and the top five principal components of the population stratification analysis. The x axis represents chromosomal locations and the y axis shows P values on a logarithmic scale.

Figure 2. Association and linkage disequilibrium plot of the 9q34 locus

Association results are shown for all GWAS studies (blue diamonds), GWAS cohorts (green diamonds), replication studies (red circles) and all studies combined (yellow circles). Overlaid on the association panel is a plot of estimated recombination rates (cM/Mb) across the region from HapMap Phase II. The LD plot shows a region of chromosome 9 marked by SNPs, rs505922 and rs630014 (r²=0.52 in HapMap CEU and 0.40 in PanScan European control individuals) and bounded by SNPs between chr9; 135,083,020-135,176,984 (NCBI Genome build 36). LD is depicted for SNPs with MAF > 5% within PanScan. Controls of European background (n=1,799 unrelated individuals). Note that rs505922 and rs630014 are located in the first intron of the ABO gene, shown above the LD plot. Only SNPs genotyped in both the GWAS and “Fast Track” replication are shown.