Most complex diseases are regulated by many causative variants that independently show only a small effect on the trait. These effects could easily be missed in a standard genome-wide association study (GWAS). However, even though the individual effect of each SNP is low, collectively they might account for a substantial proportion of variation. This implies that, as a complement to GWAS, we can gain information about the genetic architecture by combining effects across SNPs.
Our aim was to estimate the variance explained (heritability) for esophageal adenocarcinoma (EA), a rapidly fatal cancer, and its main precursor Barrett’s esophagus (BE) when including all genotyped SNPs. We used a new method developed to estimate variance explained for case-control studies of unrelated individuals1 . We also examined if EA and BE share a similar genetic background by using a large number of SNPs in one trait to predict the risk of developing the other trait2. Systematic evaluation of the overlap between the traits is based on “profile” scores, for which we calculated the estimated relative risk for every SNP based on a ‘discovery’ set (BE) and then tested this “profile’ in a target set of interest (EA).
Our results, based on 1503 EA cases, 2383 BE cases and 3202 controls, show a significant variance explained for both EA (0.28, se=0.05) and BE (0.39, se=0.05) when including all genotyped SNPs. We also found a substantial polygenetic overlap between EA and BE (p=1e-12). Given this overlap, we expect combining EA and BE as a larger case set versus all controls will improve power to map some loci. Examination of other risk factors showed that the genetic overlap was larger for patients with low BMI and non smokers. These results suggest that the genetic architecture for both diseases consist of many common variants, each of small effect, and the diseases seem to have a shared genetic background.