Evaluation of population stratification adjustment using genome-wide or exonic variants

Population stratification may cause an inflated type-I error and spurious association when assessing the association between genetic variations with an outcome. Many genetic association studies are now using exonic variants, which captures only 1% of the genome, however, population stratification adjustments have not been evaluated in the context of exonic variants. We compare the performance of two established approaches: principal components analysis (PCA) and mixed-effects models and assess the utility of genome-wide (GW) and exonic variants, by simulation and using a data set from the Framingham Heart Study. Our results illustrate that although the PCs and genetic relationship matrices computed by GW and exonic markers are different, the type-I error rate of association tests for common variants with additive effect appear to be properly controlled in the presence of population stratification. In addition, by considering single nucleotide variants (SNVs) that have different levels of confounding by population stratification, we also compare the power across multiple association approaches to account for population stratification such as PC-based corrections and mixed-effects models. We find that while these two methods achieve a similar power for SNVs that have a low or medium level of confounding by population stratification, mixed-effects model can reach a higher power for SNVs highly confounded by population stratification.