Control of confounding of genetic associations in stratified populations
Open accessAbstract
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.
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Several candidate-gene admixture studies on African Americans and African Caribbeans have shown that the same three nonsynonymous polymorphisms found in the South Asian cohort-rs1042602 in TYR, rs16891982 in SLC45A2, and rs1426654 in SLC24A5-are significantly associated with melanin content measured by reflectometry.
“During the past few years, several candidate-gene admixture studies on a cohort of African Americans and African Caribbeans has shown that the same three nonsynonymous polymorphisms that we found in our South Asian cohort-rs1042602 in TYR, rs16891982 in SLC45A2, and rs1426654 in SLC24A5-are significantly associated with melanin content measured by reflectometry.13,21,22,24”
From A Genomewide Association Study of Skin Pigmentation in a South Asian Population (2007) · cites this paper as [21]
The TYR SNP rs1042602 is highly polymorphic in all European populations, but previous studies found that this SNP was not significantly associated with skin-reflectance measurements in a white population.
“In comparison, the TYR SNP rs1042602 is highly polymorphic in all European populations, but, despite its variability, previous studies found that this SNP was not significantly associated with skin-reflectance measurements in a white population.13,21,24,29”
From A Genomewide Association Study of Skin Pigmentation in a South Asian Population (2007) · cites this paper as [21]
Cites
Gelman, A., Carlin, J. B., Stern, H. S., Dunson, D. B., Vehtari, A., & Rubin, D. B. (2013) · doi:10.1201/b16018 · Cited by 27,276 · see citing works
Statistical Analysis With Missing Data
Lahiff, M., Little, R. J. A., & Rubin, D. B. (1989) · Journal of the American Statistical Association · doi:10.2307/2289883 · Cited by 17,384 · see citing works
Genomic Control for Association Studies
Devlin, B., & Roeder, K. (1999) · Biometrics · doi:10.1111/j.0006-341x.1999.00997.x · Cited by 3,162 · see citing works
Statistical Analysis with Missing Data.
Chatfield, C., Little, R. J. A., & Rubin, D. B. (1988) · Journal of the Royal Statistical Society Series A (Statistics in Society) · doi:10.2307/2982783 · Cited by 2,203 · see citing works
Association mapping in structured populations.
Pritchard, J. K., Stephens, M., Rosenberg, N., & Donnelly, P. (2000) · American Journal of Human Genetics · doi:10.1086/302959 · Cited by 2,066 · see citing works
Score Tests for Association between Traits and Haplotypes when Linkage Phase Is Ambiguous
Schaid, D. J., Rowland, C. M., Tines, D. E., Jacobson, R. M., & Poland, G. A. (2002) · The American Journal of Human Genetics · doi:10.1086/338688 · Cited by 1,772 · see citing works
Bayesianly Justifiable and Relevant Frequency Calculations for the Applied Statistician
Rubin, D. (1984) · The Annals of Statistics · doi:10.1214/aos/1176346785 · Cited by 1,503 · see citing works
Association study designs for complex diseases
Cardon, L. R., & Bell, J. I. (2001) · Nature Reviews Genetics · doi:10.1038/35052543 · Cited by 1,380 · see citing works
Fearn, T., Gelman, A., Carlin, J., Stern, H., & Rubin, D. B. (1996) · Biometrics · doi:10.2307/2533081 · Cited by 1,322 · see citing works
Problems of reporting genetic associations with complex outcomes
Colhoun, H. M., McKeigue, P., & Smith, G. D. (2003) · The Lancet · doi:10.1016/s0140-6736(03)12715-8 · Cited by 1,203 · see citing works
Self-citationPopulation stratification and spurious allelic association
Cardon, L. R., & Palmer, L. J. (2003) · The Lancet · doi:10.1016/s0140-6736(03)12520-2 · Cited by 1,189 · see citing works
Estimating African American Admixture Proportions by Use of Population-Specific Alleles
Parra, E. J., Marcini, A., Akey, J., Martinson, J., Batzer, M. A., Cooper, R., Forrester, T., Allison, D. B., Deka, R., Ferrell, R. E., et al. (1998) · The American Journal of Human Genetics · doi:10.1086/302148 · Cited by 771 · cited 3× · see citing works
“In a recently admixed population, covariance of ancestry between linked loci may give rise to associations of the trait with alleles or haplotypes at loci 20 cM from a trait locus (Parra et al. 1998).”
BackgroundInfluentialSelf-citationA Sibship Test for Linkage in the Presence of Association: The Sib Transmission/Disequilibrium Test
Spielman, R. S., & Ewens, W. J. (1998) · The American Journal of Human Genetics · doi:10.1086/301714 · Cited by 666 · see citing works
A Generalization of the Transmission/Disequilibrium Test for Uncertain-Haplotype Transmission
Clayton, D. G. (1999) · The American Journal of Human Genetics · doi:10.1086/302577 · Cited by 634 · see citing works
Self-citationSkin pigmentation, biogeographical ancestry and admixture mapping
Shriver, M. D., Parra, E. J., Dios, S., Bonilla, C., Norton, H., Jovel, C., Pfaff, C., Jones, C., Massac, A., Cameron, N., et al. (2003) · Human Genetics · doi:10.1007/s00439-002-0896-y · Cited by 549 · see citing works
Self-citationPopulation genetic structure of variable drug response
Wilson, J. F., Weale, M. E., Smith, A. C., Gratrix, F., Fletcher, B., Thomas, M., Bradman, N. N., & Goldstein, D. B. (2001) · Nature Genetics · doi:10.1038/ng761 · Cited by 460 · see citing works
Griscelli disease maps to chromosome 15q21 and is associated with mutations in the Myosin-Va gene
Pastural, É., Barrat, F. J., Dufourcq-Lagelouse, R., Dogniaux, S., Sanal, Ö., Jabado, N., Seger, R. A., Griscelli, C., Fischer, A., & Basile, G. D. S. (1997) · Nature Genetics · doi:10.1038/ng0797-289 · Cited by 453 · see citing works
Fallin, M. D., & Schork, N. J. (2000) · The American Journal of Human Genetics · doi:10.1086/303069 · Cited by 405 · see citing works
Case–Control Studies of Association in Structured or Admixed Populations
Pritchard, J. K., & Donnelly, P. (2001) · Theoretical Population Biology · doi:10.1006/tpbi.2001.1543 · Cited by 397 · see citing works
Point: population stratification: a problem for case-control studies of candidate-gene associations?
Thomas, D. C., & Witte, J. S. (2002) · PubMed · Cited by 391 · see citing works
Mapping disease genes: family-based association studies.
Thomson, G. (1995) · PubMed Central · Cited by 335 · see citing works
(1999) · Nature Genetics · doi:10.1038/8702 · Cited by 264 · see citing works
Wacholder, S., Rothman, N., & Caporaso, N. E. (2002) · PubMed · Cited by 255 · see citing works
Satten, G., Flanders, W., & Yang, Q.-H. (2001) · American Journal of Human Genetics · doi:10.1086/318195 · Cited by 249 · see citing works
Tests and estimates of allelic association in complex inheritance
Morton, N. E., & Collins, A. R. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.19.11389 · Cited by 248 · see citing works
McKeigue, P. (1998) · The American Journal of Human Genetics · doi:10.1086/301908 · Cited by 231 · see citing works
Self-citationMcKeigue, P., Carpenter, J., Parra, E., & Shriver, M. (2000) · Annals of Human Genetics · doi:10.1046/j.1469-1809.2000.6420171.x · Cited by 230 · see citing works
Self-citationParameters for reliable results in genetic association studies in common disease
Dahlman, I. A., Eaves, I. A., Kosoy, R., Morrison, V., Heward, J. M., Gough, S. C. L., Allahabadia, A., Franklyn, J. A., Tuomilehto, J., Tuomilehto‐Wolf, E., et al. (2002) · Nature Genetics · doi:10.1038/ng825 · Cited by 229 · see citing works
Transmission-disequilibrium tests for quantitative traits.
Allison, D. B. (1997) · PubMed · Cited by 217 · see citing works
Transmission/disequilibrium tests for quantitative traits
Sun, F., Flanders, W. D., Yang, Q., & Zhao, H. (2000) · Annals of Human Genetics · doi:10.1046/j.1469-1809.2000.6460555.x · Cited by 172 · see citing works
Kittles, R., Chen, W., Panguluri, R. K., Ahaghotu, C., Jackson, A. G., Adebamowo, C., Griffin, R., Williams, T., Ukoli, F. A., Adams-Campbell, L., et al. (2002) · Human Genetics · doi:10.1007/s00439-002-0731-5 · Cited by 164 · see citing works
Self-citationMcKeigue, P. (1997) · PubMed · Cited by 156 · see citing works
Self-citationMelting curve analysis of SNPs (McSNP): a gel-free and inexpensive approach for SNP genotyping.
Akey, J., Sosnoski, D., Parra, E., Dios, S., Hiester, K., Su, B., Bonilla, C., Jin, L., & Shriver, M. (2001) · BioTechniques · doi:10.2144/01302tt05 · Cited by 106 · see citing works
Self-citation14 The future of genetic case-control studies
Schork, N. J., Fallin, D., Thiel, B., Xu, X., Broeckel, U., Jacob, H. J., & Cohen, D. (2001) · Advances in genetics · doi:10.1016/s0065-2660(01)42023-2 · Cited by 100 · see citing works
The estimation of admixture in racial hybrids
Elston, R. C. (1971) · Annals of Human Genetics · doi:10.1111/j.1469-1809.1956.tb01373.x · Cited by 94 · see citing works
The impact of genotyping error on haplotype reconstruction and frequency estimation
Kirk, K. M., & Cardon, L. R. (2002) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5200855 · Cited by 85 · see citing works
Effectiveness of computational methods in haplotype prediction
Xu, C., Lewis, K. F., Cantone, K. L., Khan, P., Donnelly, C., White, N. J., Crocker, N., Boyd, P. R., Zaykin, D. V., & Purvis, I. J. (2001) · Human Genetics · doi:10.1007/s00439-001-0656-4 · Cited by 84 · see citing works
Estimation of race admixture--a new method.
Chakraborty, R. (1975) · American Journal of Physical Anthropology · doi:10.1002/ajpa.1330420319 · Cited by 61 · see citing works
Relative efficiency of ambiguous vs. directly measured haplotype frequencies
Schaid, D. J. (2002) · Genetic Epidemiology · doi:10.1002/gepi.10184 · Cited by 59 · see citing works
McKeigue, P. (2000) · The American Journal of Human Genetics · doi:10.1086/316912 · Cited by 15 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans
Lamason, R. L., Mohideen, M.-A. P. K., Mest, J. R., Wong, A. C., Norton, H. L., Aros, M. C., Jurynec, M. J., Mao, X., Humphreville, V. R., Humbert, J. E., et al. (2005) · Science · doi:10.1126/science.1116238 · Cited by 1,043 · see citing works
Self-citationThe effects of human population structure on large genetic association studies
Marchini, J., Cardon, L. R., Phillips, M. S., & Donnelly, P. (2004) · Nature Genetics · doi:10.1038/ng1337 · Cited by 869 · see citing works
Smith, G. D., Lawlor, D. A., Harbord, R., Timpson, N., Day, I., & Ebrahim, S. (2007) · PLoS Medicine · doi:10.1371/journal.pmed.0040352 · Cited by 569 · see citing works
Influence of mode of delivery on gut microbiota composition in seven year old children: Table 1
Salminen, S., Gibson, G. R., McCartney, A. L., & Isolauri, E. (2004) · Gut · doi:10.1136/gut.2004.041640 · Cited by 435 · see citing works
Genetic evidence for the convergent evolution of light skin in Europeans and East Asians
Norton, H. L., Kittles, R. A., Parra, E., McKeigue, P., Mao, X., Cheng, K., Canfield, V. A., Bradley, D. G., McEvoy, B., & Shriver, M. D. (2006) · Molecular Biology and Evolution · doi:10.1093/molbev/msl203 · Cited by 410 · see citing works
Self-citationBacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis
Wang, L.-H., Fang, X.-C., & Pan, G.-Z. (2004) · Gut · doi:10.1136/gut.2003.021154 · Cited by 387 · see citing works
Miller, C. T., Beleza, S., Pollen, A. A., Schluter, D., Kittles, R. A., Shriver, M. D., & Kingsley, D. M. (2007) · Cell · doi:10.1016/j.cell.2007.10.055 · Cited by 388 · see citing works
Self-citationDiscerning the ancestry of European Americans in genetic association studies
Price, A. L., Butler, J., Patterson, N., Capelli, C., Pascali, V. L., Scarnicci, F., Ruiz-Linares, A., Groop, L., Saetta, A. A., Korkolopoulou, P., et al. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.0030236 · Cited by 327 · see citing works
A Genomewide Association Study of Skin Pigmentation in a South Asian Population
Stokowski, R. P., Pant, P. V. K., Dadd, T., Fereday, A., Hinds, D. A., Jarman, C., Filsell, W., Ginger, R. S., Green, M. R., van der Ouderaa, F. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/522235 · Cited by 315 · see citing works
Halder, I., Shriver, M., Thomas, M., Fernandez, J. R., & Frudakis, T. (2008) · Human Mutation · doi:10.1002/humu.20695 · Cited by 274 · see citing works
Self-citationBedoya, G., Montoya, P., García, J., Soto, I., Bourgeois, S., Carvajal, L., Labuda, D., Alvarez, V., Ospina, J., Hedrick, P. W., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508716103 · Cited by 264 · see citing works
Analysis and application of European genetic substructure using 300 K SNP information
Tian, C., Plenge, R. M., Ransom, M., Lee, A., Villoslada, P., Selmi, C., Klareskog, L., Pulver, A. E., Qi, L., Gregersen, P. K., et al. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.0040004 · Cited by 247 · see citing works
Implications of correlations between skin color and genetic ancestry for biomedical research
Parra, E. J., Kittles, R. A., & Shriver, M. D. (2004) · Nature Genetics · doi:10.1038/ng1440 · Cited by 220 · see citing works
Self-citationMcEvoy, B., Beleza, S., & Shriver, M. D. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl217 · Cited by 148 · see citing works
Self-citationPropper, C., Moore, G. A., Mills-Koonce, W. R., Halpern, C. T., Hill-Soderlund, A. L., Calkins, S. D., Carbone, M. A., & Cox, M. (2008) · Child Development · doi:10.1111/j.1467-8624.2008.01194.x · Cited by 142 · see citing works
Bonilla, C., Boxill, L.-A., Donald, S. A. M., Williams, T., Sylvester, N., Parra, E. J., Dios, S., Norton, H. L., Shriver, M. D., & Kittles, R. A. (2005) · Human Genetics · doi:10.1007/s00439-004-1251-2 · Cited by 138 · see citing works
Self-citationCandille, S. I., Absher, D. M., Beleza, S., Bauchet, M., McEvoy, B., Garrison, N. A., Li, J. Z., Myers, R. M., Barsh, G. S., Tang, H., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048294 · Cited by 111 · see citing works
Self-citationGenetic determination of the hypothalamic–pituitary–thyroid axis: where do we stand?
Medici, M., Visser, W. E., Visser, T. J., & Peeters, R. P. (2015) · Endocrine Reviews · doi:10.1210/er.2014-1081 · Cited by 92 · see citing works
Measuring and using admixture to study the genetics of complex diseases
Halder, I., & Shriver, M. D. (2003) · Human Genomics · doi:10.1186/1479-7364-1-1-52 · Cited by 93 · see citing works
Self-citationAdmixture analysis of a rural population of the state of Guerrero, Mexico
Bonilla, C., Gutiérrez, G., Parra, E. J., Kline, C., & Shriver, M. D. (2005) · American Journal of Physical Anthropology · doi:10.1002/ajpa.20227 · Cited by 88 · see citing works
Self-citationGeneralized Analysis of Molecular Variance
Nievergelt, C. M., Libiger, O., & Schork, N. J. (2007) · PLoS Genetics · doi:10.1371/journal.pgen.0030051 · Cited by 80 · see citing works
Dixon, C. I., Morris, H. V., Breen, G., Desrivieres, S., Jugurnauth, S., Steiner, R. C., Vallada, H., Guindalini, C., Laranjeira, R., Messas, G., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910117107 · Cited by 77 · see citing works
Contreras-Ruiz, L., Ryan, D. S., Sia, R. K., Bower, K. S., Dartt, D. A., & Masli, S. (2014) · Ophthalmology · doi:10.1016/j.ophtha.2014.01.033 · Cited by 58 · see citing works
Wang, H., Haiman, C. A., Kolonel, L. N., Henderson, B. E., Wilkens, L. R., Le Marchand, L., & Stram, D. O. (2010) · Human Genetics · doi:10.1007/s00439-010-0841-4 · Cited by 45 · see citing works
- Authors
- Hoggart, C. J., Parra, E. J., Shriver, M. D., Bonilla, C., Kittles, R. A., Clayton, D. G., & McKeigue, P. M.
- Affiliations
- London School of Hygiene & Tropical Medicine (GB)
- Pennsylvania State University (US)
- Howard University (US)
- University of Cambridge (GB)
- Corresponding author
- Hoggart, Clive J.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2003-06
- Volume
- 72
- Issue
- 6
- Pages
- 1492-1504
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1180309
- OpenAlex
- W2108214367
- Cited by
- 490
- References
- 42
- Citations by year
- 2026: 2 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 12 · 2017: 11 · 2016: 17 · 2015: 21 · 2014: 26 · 2013: 32 · 2012: 37
- FWCI
- 21.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (submittedVersion)
- Funders
- Wellcome Trust
- National Institutes of Health (5r01mh060343-03)
- National Institute of Mental Health (MH 60343)
- National Human Genome Research Institute (R01HG002154, HG-02154)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK53958, R01DK053958)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic diversity and population structure
- Keywords
- population stratification, confounding, genetic association studies, admixture, ancestry inference, skin pigmentation, selection bias, African Americans, African Caribbeans, ancestry informative markers, Bayesian analysis
- MeSH terms
- Bayes Theorem, Black or African American, Female, Genetic Markers, Genetics, Population, Genotype, Humans, Male, Markov Chains, Models, Genetic, Monte Carlo Method, Polymorphism, Genetic, Skin Pigmentation, Confounding Factors, Epidemiologic, Case-Control Studies, Quantitative Trait, Heritable, Black People, White People
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