Control of confounding of genetic associations in stratified populations

Clive J. Hoggart, Esteban J. Parra, Mark D. Shriver, Carolina Bonilla, Rick A Kittles, David G. Clayton, Paul M. McKeigue

Research output: Contribution to journalArticle

392 Citations (Scopus)

Abstract

To control for hidden population stratification in genetic-association studies, statistical methods that use marker genotype data to infer population structure have been proposed as a possible alternative to family-based designs. In principle, it is possible to infer population structure from associations between marker loci and from associations of markers with the trait, even when no information about the demographic background of the population is available. In a model in which the total population is formed by admixture between two or more subpopulations, confounding can be estimated and controlled. Current implementations of this approach have limitations, the most serious of which is that they do not allow for uncertainty in estimations of individual admixture proportions or for lack of identifiability of subpopulations in the model. We describe methods that overcome these limitations by a combination of Bayesian and classical approaches, and we demonstrate the methods by using data from three admixed populations - African American, African Caribbean, and Hispanic American - in which there is extreme confounding of trait-genotype associations because the trait under study (skin pigmentation) varies with admixture proportions. In these data sets, as many as one-third of marker loci show crude associations with the trait. Control for confounding by population stratification eliminates these associations, except at loci that are linked to candidate genes for the trait. With only 32 markers informative for ancestry, the efficiency of the analysis is ∼70%. These methods can deal with both confounding and selection bias in genetic-association studies, making family-based designs unnecessary.

Original languageEnglish (US)
Pages (from-to)1492-1504
Number of pages13
JournalAmerican Journal of Human Genetics
Volume72
Issue number6
DOIs
StatePublished - Jun 1 2003
Externally publishedYes

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Population
Genetic Association Studies
African Americans
Genotype
Skin Pigmentation
Bayes Theorem
Selection Bias
Hispanic Americans
Uncertainty
Demography
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Hoggart, C. J., Parra, E. J., Shriver, M. D., Bonilla, C., Kittles, R. A., Clayton, D. G., & McKeigue, P. M. (2003). Control of confounding of genetic associations in stratified populations. American Journal of Human Genetics, 72(6), 1492-1504. https://doi.org/10.1086/375613

Control of confounding of genetic associations in stratified populations. / Hoggart, Clive J.; Parra, Esteban J.; Shriver, Mark D.; Bonilla, Carolina; Kittles, Rick A; Clayton, David G.; McKeigue, Paul M.

In: American Journal of Human Genetics, Vol. 72, No. 6, 01.06.2003, p. 1492-1504.

Research output: Contribution to journalArticle

Hoggart, CJ, Parra, EJ, Shriver, MD, Bonilla, C, Kittles, RA, Clayton, DG & McKeigue, PM 2003, 'Control of confounding of genetic associations in stratified populations', American Journal of Human Genetics, vol. 72, no. 6, pp. 1492-1504. https://doi.org/10.1086/375613
Hoggart, Clive J. ; Parra, Esteban J. ; Shriver, Mark D. ; Bonilla, Carolina ; Kittles, Rick A ; Clayton, David G. ; McKeigue, Paul M. / Control of confounding of genetic associations in stratified populations. In: American Journal of Human Genetics. 2003 ; Vol. 72, No. 6. pp. 1492-1504.
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