Population stratification

Population stratification is the presence of a systematic difference in allele frequencies between subpopulations in a population possibly due to different ancestry, especially in the context of association studies. Population stratification is also referred to as population structure, in this context.

The basic cause of population stratification is nonrandom mating between groups, often due to their physical separation (e.g., for populations of African and European descent) followed by genetic drift of allele frequencies in each group. In some contemporary populations there has been recent admixture between individuals from different populations, leading to populations in which ancestry is variable (as in African Americans). Over tens of generations, random mating can eliminate this type of stratification. In some parts of the globe (e.g., in Europe), population structure is best modeled by isolation-by-distance, in which allele frequencies tend to vary smoothly with location.

Population stratification can be a problem for association studies, such as case-control studies, where the association could be found due to the underlying structure of the population and not a disease associated locus. By analogy, one might imagine a scenario in which certain small beads are made out of a certain type of unique foam, and that children tend to choke on these beads; one might wrongly conclude that the foam material causes choking when in fact it is the small size of the beads. Also the real disease causing locus might not be found in the study if the locus is less prevalent in the population where the case subjects are chosen. For this reason, it was common in the 1990s to use family-based data where the effect of population stratification can easily be controlled for using methods such as the TDT. But if the structure is known or a putative structure is found, there are a number of possible ways to implement this structure in the association studies and thus compensate for any population bias. Most contemporary genome-wide association studies take the view that the problem of population stratification is manageable, and that the logistic advantages of using unrelated cases and controls make these studies preferable to family-based association studies.

The two most widely used approaches to this problem include genomic control, which is a relatively nonparametric method for controlling the inflation of test statistics, and structured association methods, which use genetic information to estimate and control for population structure. Currently, the most widely used structured association method is Eigenstrat, developed by Alkes Price and colleagues.

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