Concealed effects of gene-environment interactions in genome-wide association

Genome-wide association studies (GWAS) have been conducted on many complex diseases with the aim of identifying common genetic variants important in disease susceptibility. It is rare for these to consider environmental factors when calculating the odds ratios for variants associated with disease. We modelled the effect of an environmentally-dependent genetic risk locus and showed that, despite a relatively low overall odds ratio, environmental exposure was able to conceal a large true effect size on disease susceptibility in exposed individuals. This model was applied to vitamin D deficiency in multiple sclerosis and raised the possibility of large magnitudes of concealed effect in loci responsive to vitamin D in this disease. In the post-GWAS era, efforts should be made to elucidate potential gene-environment interactions involved in complex traits in order for true effects on disease risk to be realised.