Overdispersion of allele frequency differences between populations: implications for meta-analyses of genotypic disease associations

Methods correcting case-control studies of genetic polymorphisms for unmeasured genetic population substructure by modelling the variation at a number of variant loci provide no standard and easily implemented approach to meta-analysis, which is a key to understanding the effects of minor genotypic risks on complex diseases. A correction of the odds ratio estimate and its confidence interval is shown to be easy to implement using a mixed effects logistic regression. The method is shown to substantially reduce bias and to give accurate coverage even when there is substantial overdispersion of allele frequency differences between populations. Major sequence classes of single-nucleotide polymorphism (SNP) are likely to act as valid controls for each other, since CpG SNPs did not differ in the extent of population structure from other SNPs. Agreement among investigators and journals to provide these straightforward statistics in publications of polymorphism studies will enhance the ability of future investigators to perform meta-analyses of weak genetic effects across accumulated studies that allow for population structure.