The current study provides additional insight into European substructure and differences among different ethnic groups that may impact our understanding of the genetics of complex diseases. First, together with our recent report of a whole genome association study for RA in European Americans, this report emphasizes the importance of controlling for substructure in the ascertainment of putative susceptibility associated SNPs. Most notably without an analysis of substructure, IRF4 would appear as a very strong candidate for this disease. However, the large differences in allele frequency for this gene are largely due to the difference in allele frequency among different European subpopulation groups. Furthermore, this difference is accentuated when the northern population subgroup is examined. When only NYCP controls are considered an IRF4 SNP (rs12203592) showed the largest allele frequency difference between the Irish individuals and those individuals of Northern, Central European and Eastern European descent (δ = 0.40, Fst = 0.27). Using an algorithm based on the PCs, EIGENSTRAT, this SNP no longer appears significantly associated with RA. The difference in allele frequency for IRF4 within European populations has recently also been described by the Welcome Trust Case Control Consortium study [26].
