“Population stratification”的意思、由来-开放百科全书

Population stratification (or population structure) 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.

Causes

The basic cause of population stratification is non-random 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). 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.

Association studies

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 Transmission disequilibrium test (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,^[1] 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,^[2] and structured association methods,^[3] 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.^[4]

Genomic control

The assumption of population homogeneity in association studies, especially case-control

studies, can easily be violated and can lead to both type I and type II errors. It is

therefore important for the models used in the study to compensate for the population

structure. The problem in case control studies is that if there is a genetic involvement in

the disease, the case population is more likely to be related than the individuals in the

control population. This means that the assumption of independence of observations is

violated. Often this will lead to an overestimation of the significance of an association

but it depends on the way the sample was chosen. If, coincidentally, there is a higher allele

frequency in a subpopulation of the cases, you will find association with any trait that is more prevalent

increases as the sample population grows so the problem should be of special concern in

large scale association studies when loci only cause relatively small effects on the trait. A method that in some cases can compensate for the above described problems has been developed by Devlin and

Roeder (1999).^[6] It uses both a frequentist and a Bayesian approach (the latter being

The frequentist way of correcting for population stratification works by using markers that are not linked with the trait in question to correct

for any inflation of the statistic caused by population stratification. The method was

first developed for binary traits but has since been generalized for quantitative ones.^[7] For the binary one, which applies to finding genetic differences

between the case and control populations, Devlin and Roeder (1999) use Armitage's trend test

If the population is in Hardy-Weinberg equilibrium the two statistics are approximately

equal. Under the null hypothesis of no population stratification the trend test is

The idea is that the statistic is inflated by a factor

so that

where

depends on the effect of stratification. The above method rests upon the assumptions that the inflation

factor

is constant, which means that the loci should have roughly equal mutation

rates, should not be under different selection in the two populations, and the amount of

Hardy-Weinberg disequilibrium measured in Wright’s coefficient of inbreeding F should

not differ between the different loci. The last of these is of greatest concern. If the effect of

the stratification is similar across the different loci

can be estimated from the unlinked

is derived from the gamma distribution as a robust estimator of

. Other estimators have been suggested, for example, Reich and Goldstein^[8] suggested using the mean of the statistics instead.

This is not the only way to estimate

but according to Bacanu et al.^[9] it is an

appropriate estimate even if some of the unlinked markers are actually in disequilibrium

with a disease causing locus or are themselves associated with the disease. Under the

null hypothesis and when correcting for stratification using L unlinked genes,

overall type I error rate should be approximately equal to

even when the population

95% confidence level and not smaller p-values. Marchini et al. (2004)^[11] demonstrates by

simulation that genomic control can lead to an anti-conservative p-value if this value

is very small and the two populations (case and control) are extremely distinct. This

was especially a problem if the number of unlinked markers were in the order 50 − 100.

Demographic inference

Population structure is also an important aspect of evolutionary and population genetics. Many statistical methods rely on simple population models in order to infer historical demographic changes, such as the presence of population bottlenecks, admixture events or population divergence times. Often these methods rely on the assumption of panmictia, or homogeneity in an ancestral population. Recent studies have shown that the misspecification of such models, for instance by not taking into account the existence of structure in an ancestral population, can give rise to heavily biased parameter estimates.^[12] Mounting evidence from simulation studies show that historical population structure can even have genetic effects that can easily be misinterpreted as historical changes in population size, or the existence of admixture events, even when no such events occurred.^[13]

References

1. ^Pritchard, J.K. and Rosenberg, N.A. (1999). Use of unlinked genetic markers to detect population stratification in association studies. American Journal of Human Genetics 65:220-228. [https://doi.org/10.1086/302449 doi]
2. ^Devlin, B. and Roeder, K. (1999). Genomic control for association studies, Biometrics55(4): 997–1004.
3. ^Pritchard, JK, Stephens, M, Rosenberg NA, and Donnelly P. (2000) Association mapping in structured populations. American Journal of Human Genetics 67: 170-181
4. ^Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. (2006) Principal components analysis corrects for stratification in genome-wide association. Nature Genetics 38:904-909
5. ^Lander, E. S. and Schork, N. J. (1994). Genetic dissection of complex traits, Science 265(5181): 2037–2048.
6. ^Devlin, B. and Roeder, K. (1999). Genomic control for association studies, Biometrics55(4): 997–1004.
7. ^Bacanu, S.-A., Devlin, B. and Roeder, K. (2002). Association studies for quantitativetraits in structured populations, Genet Epidemiol 22(1): 78–93.
8. ^Reich, D. E. and Goldstein, D. B. (2001). Detecting association in a case-control study while correcting for population stratification, Genet Epidemiol 20(1): 4–16.
9. ^Bacanu, S. A., Devlin, B. and Roeder, K. (2000). The power of genomic control, Am JHum Genet 66(6): 1933–1944.
10. ^Devlin, B. and Roeder, K. (1999). Genomic control for association studies, Biometrics55(4): 997–1004.
11. ^Marchini, J., Cardon, L. R., Phillips, M. S. and Donnelly, P. (2004). The effects of humanpopulation structure on large genetic association studies, Nat Genet 36(5): 512–517.
12. ^{{Cite journal|last=Scerri|first=Eleanor M.L.|last2=Thomas|first2=Mark G.|last3=Manica|first3=Andrea|last4=Gunz|first4=Philipp|last5=Stock|first5=Jay T.|last6=Stringer|first6=Chris|last7=Grove|first7=Matt|last8=Groucutt|first8=Huw S.|last9=Timmermann|first9=Axel|date=August 2018|title=Did Our Species Evolve in Subdivided Populations across Africa, and Why Does It Matter?|url=https://linkinghub.elsevier.com/retrieve/pii/S0169534718301174|journal=Trends in Ecology & Evolution|volume=33|issue=8|pages=582–594|doi=10.1016/j.tree.2018.05.005}}
13. ^{{Cite journal|last=Rodríguez|first=Willy|last2=Mazet|first2=Olivier|last3=Grusea|first3=Simona|last4=Arredondo|first4=Armando|last5=Corujo|first5=Josué M.|last6=Boitard|first6=Simon|last7=Chikhi|first7=Lounès|date=December 2018|title=The IICR and the non-stationary structured coalescent: towards demographic inference with arbitrary changes in population structure|url=http://www.nature.com/articles/s41437-018-0148-0|journal=Heredity|volume=121|issue=6|pages=663–678|doi=10.1038/s41437-018-0148-0|issn=0018-067X|pmc=6221895|pmid=30293985}}