Population Stratification in Genetic Association Studies

Jacklyn N. Hellwege1, Jacob M. Keaton1, Ayush Giri1, Xiaoyi Gao2, Digna R. Velez Edwards3, Todd L. Edwards1

1 Vanderbilt Genetics Institute, Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 2 Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, 3 Vanderbilt Genetics Institute, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee
Publication Name:  Current Protocols in Human Genetics
Unit Number:  Unit 1.22
DOI:  10.1002/cphg.48
Online Posting Date:  October, 2017
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Population stratification (PS) is a primary consideration in studies of genetic determinants of human traits. Failure to control for PS may lead to confounding, causing a study to fail for lack of significant results, or resources to be wasted following false‐positive signals. Here, historical and current approaches for addressing PS when performing genetic association studies in human populations are reviewed. Methods for detecting the presence of PS, including global and local ancestry methods, are described. Also described are approaches for accounting for PS when calculating association statistics, such that measures of association are not confounded. Many traits are being examined for the first time in minority populations, which may inherently feature PS. © 2017 by John Wiley & Sons, Inc.

Keywords: admixture; admixture mapping; association confounding; global ancestry; local ancestry; population stratification

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Table of Contents

  • Key Concepts
  • Quantifying Population Stratification
  • Strategy
  • Conclusion
  • Literature Cited
  • Figures
  • Tables
PDF or HTML at Wiley Online Library


PDF or HTML at Wiley Online Library



Literature Cited

Literature Cited
  Abraham, G. & Inouye, M. (2014). Fast principal component analysis of large‐scale genome‐wide data. PLoS One, 9(4), e93766. doi: 10.1371/journal.pone.0093766.
  Alexander, D. H. & Lange, K. (2011). Enhancements to the ADMIXTURE algorithm for individual ancestry estimation. BMC Bioinformatics, 12, 246. doi: 10.1186/1471‐2105‐12‐246.
  Alexander, D. H., Novembre, J., & Lange, K. (2009). Fast model‐based estimation of ancestry in unrelated individuals. Genome Research, 19(9), 1655–1664. doi: 10.1101/gr.094052.109.
  Astle, W. & Balding, D. J. (2009). Population structure and cryptic relatedness in genetic association studies. Statistical Science, 24(4), 451–471. doi: 10.1214/09‐STS307.
  Bacanu, S. A., Devlin, B., & Roeder, K. (2002). Association studies for quantitative traits in structured populations. Genetic Epidemiology, 22(1), 78–93. doi: 10.1002/gepi.1045.
  Baran, Y., Pasaniuc, B., Sankararaman, S., Torgerson, D. G., Gignoux, C., Eng, C., … Halperin, E. (2012). Fast and accurate inference of local ancestry in Latino populations. Bioinformatics (Oxford, England), 28, 1359–1367. doi: 10.1093/bioinformatics/bts144.
  Bayless, T. M., Brown, E., & Paige, D. M. (2017). Lactase non‐persistence and lactose intolerance. Current Gastroenterology Reports, 19(5), 23. doi: 10.1007/s11894‐017‐0558‐9.
  Bell, G. I., Horita, S., & Karam, J. H. (1984). A polymorphic locus near the human insulin gene is associated with insulin‐dependent diabetes mellitus. Diabetes, 33(2), 176–183. doi: 10.2337/diab.33.2.176.
  Benn‐Torres, J., Bonilla, C., Robbins, C. M., Waterman, L., Moses, T. Y., Hernandez, W., … Kittles, R. A. (2008). Admixture and population stratification in African Caribbean populations. Annals of Human Genetics, 72(Pt 1), 90–98. doi: 10.1111/j.1469‐1809.2007.00398.x
  Bersaglieri, T., Sabeti, P. C., Patterson, N., Vanderploeg, T., Schaffner, S. F., Drake, J. A., … Hirschhorn, J. N. (2004). Genetic signatures of strong recent positive selection at the lactase gene. American Journal of Human Genetics, 74(6), 1111–1120. doi: 10.1086/421051.
  Bhaskar, A., Javanmard, A., Courtade, T. A., & Tse, D. (2017). Novel probabilistic models of spatial genetic ancestry with applications to stratification correction in genome‐wide association studies. Bioinformatics (Oxford, England), 33(6), 879–885. doi: 10.1093/bioinformatics/btw720
  Bhatia, G., Furlotte, N. A., Loh, P.‐R., Liu, X., Finucane, H. K., Gusev, A., & Price, A. (2016). Correcting subtle stratification in summary association statistics. bioRxiv, 076133. doi: https://doi.org/10.1101/076133
  Bhatia, G., Gusev, A., Loh, P‐R., Finucane, H. K., Vilhjalmsson, B. J., Ripke, S., … Price, A. L. (2016). Subtle stratification confounds estimates of heritability from rare variants. bioRxiv, doi: https://doi.org/10.1101/048181
  Bomblies, K., Yant, L., Laitinen, R. A., Kim, S. T., Hollister, J. D., Warthmann, N., … Weigel, D. (2010). Local‐scale patterns of genetic variability, outcrossing, and spatial structure in natural stands of Arabidopsis thaliana. PLoS Genetics, 6(3), e1000890. doi: 10.1371/journal.pgen.1000890.
  Browning, S. R., & Thompson, E. A. (2012). Detecting rare variant associations by identity‐by‐descent mapping in case‐control studies. Genetics, 190(4), 1521–1531. doi: 10.1534/genetics.111.136937.
  Brucato, N., Tortevoye, P., Plancoulaine, S., Guitard, E., Sanchez‐Mazas, A., Larrouy, G., … Dugoujon, J. M. (2009). The genetic diversity of three peculiar populations descending from the slave trade: Gm study of Noir Marron from French Guiana. Comptes Rendus Biologies, 332(10), 917–926. doi: 10.1016/j.crvi.2009.07.005.
  Bryc, K., Auton, A., Nelson, M. R., Oksenberg, J. R., Hauser, S. L., Williams, S., … Tishkoff, S. A. (2010). Genome‐wide patterns of population structure and admixture in West Africans and African Americans. Proceedings of the National Academy of Sciences of the United States of America, 107(2), 786–791. doi: 10.1073/pnas.0909559107.
  Bryc, K., Durand, E. Y., Macpherson, J. M., Reich, D., & Mountain, J. L. (2015). The genetic ancestry of African Americans, Latinos, and European Americans across the United States. American Journal of Human Genetics, 96(1), 37–53. doi: 10.1016/j.ajhg.2014.11.010.
  Bulik‐Sullivan, B. K., Loh, P. R., Finucane, H. K., Ripke, S., Yang, J., Patterson, N., … Neale, B. M. (2015). LD Score regression distinguishes confounding from polygenicity in genome‐wide association studies. Nature Genetics, 47(3), 291–295. doi: 10.1038/ng.3211.
  Campbell, C. D., Ogburn, E. L., Lunetta, K. L., Lyon, H. N., Freedman, M. L., Groop, L. C., … Hirschhorn, J. N. (2005). Demonstrating stratification in a European American population. Nature Genetics, 37(8), 868–872. doi: 10.1038/ng1607.
  Cardon, L. R., & Palmer, L. J. (2003). Population stratification and spurious allelic association. Lancet, 361(9357), 598–604. doi: 10.1016/S0140‐6736(03)12520‐2.
  Carmi, S., Hui, K. Y., Kochav, E., Liu, X., Xue, J., Grady, F., … Pe'er, I. (2014). Sequencing an Ashkenazi reference panel supports population‐targeted personal genomics and illuminates Jewish and European origins. Nature Communications, 5, 4835. doi: 10.1038/ncomms5835.
  Chen, C. Y., Pollack, S., Hunter, D. J., Hirschhorn, J. N., Kraft, P., & Price, A. L. (2013). Improved ancestry inference using weights from external reference panels. Bioinformatics (Oxford, England), 29(11), 1399–1406. doi: 10.1093/bioinformatics/btt144.
  Cheng, Y. J., Mailund, T., & Nielsen, R. (2017). Fast admixture analysis and population tree estimation for SNP and NGS data. Bioinformatics (Oxford, England), 33(14), 2148–2155. doi: 10.1093/bioinformatics/btx098.
  Choudhry, S., Coyle, N. E., Tang, H., Salari, K., Lind, D., Clark, S. L., … Genetics of Asthma in Latino Americans GALA Study (2006). Population stratification confounds genetic association studies among Latinos. Human Genetics, 118(5), 652–664. doi: 10.1007/s00439‐005‐0071‐3.
  Chung, R. H., Schmidt, M. A., Morris, R. W., & Martin, E. R. (2010). CAPL: A novel association test using case‐control and family data and accounting for population stratification. Genetic Epidemiology, 34(7), 747–755. doi: 10.1002/gepi.20539.
  Conomos, M. P., Miller, M. B., & Thornton, T. A. (2015). Robust inference of population structure for ancestry prediction and correction of stratification in the presence of relatedness. Genetic Epidemiology, 39(4), 276–293. doi: 10.1002/gepi.21896.
  Dadd, T., Weale, M. E., & Lewis, C. M. (2009). A critical evaluation of genomic control methods for genetic association studies. Genetic Epidemiology, 33(4), 290–298. doi: 10.1002/gepi.20379.
  Dandine‐Roulland, C., Bellenguez, C., Debette, S., Amouyel, P., Genin, E., & Perdry, H. (2016). Accuracy of heritability estimations in presence of hidden population stratification. Scientific Reports, 6, 26471. doi: 10.1038/srep26471.
  Deelen, P., Menelaou, A., van Leeuwen, E. M., Kanterakis, A., van Dijk, F., Medina‐Gomez, C., … Swertz, M. A. (2014). Improved imputation quality of low‐frequency and rare variants in European samples using the ‘Genome of The Netherlands’. European Journal of Human Genetics, 22(11), 1321–1326. doi: 10.1038/ejhg.2014.19.
  Devlin, B., Bacanu, S. A., & Roeder, K. (2004). Genomic control to the extreme. Nature Genetics, 36(11), 1129–1130; author reply 1131. doi: 10.1038/ng1104‐1129.
  Devlin, B., & Roeder, K. (1999). Genomic control for association studies. Biometrics, 55(4), 997–1004. doi: 10.1111/j.0006‐341X.1999.00997.x.
  Devlin, B., Roeder, K., & Wasserman, L. (2001). Genomic control, a new approach to genetic‐based association studies. Theoretical Population Biology, 60(3), 155–166. doi: 10.1006/tpbi.2001.1542.
  Enattah, N. S., Sahi, T., Savilahti, E., Terwilliger, J. D., Peltonen, L., & Jarvela, I. (2002). Identification of a variant associated with adult‐type hypolactasia. Nature Genetics, 30(2), 233–237. doi: 10.1038/ng826.
  Epstein, M. P., Allen, A. S., & Satten, G. A. (2007). A simple and improved correction for population stratification in case‐control studies. American Journal of Human Genetics, 80(5), 921–930. doi: 10.1086/516842.
  Eriksson, N., Macpherson, J. M., Tung, J. Y., Hon, L. S., Naughton, B., Saxonov, S., … Mountain, J. (2010). Web‐based, participant‐driven studies yield novel genetic associations for common traits. PLoS Genetics, 6(6), e1000993. doi: 10.1371/journal.pgen.1000993.
  Falush, D., Stephens, M., & Pritchard, J. K. (2003). Inference of population structure using multilocus genotype data: Linked loci and correlated allele frequencies. Genetics, 164(4), 1567–1587.
  Franceschini, N., Fox, E., Zhang, Z., Edwards, T. L., Nalls, M. A., Sung, Y. J., … Zhu, X. (2013). Genome‐wide association analysis of blood‐pressure traits in African‐ancestry individuals reveals common associated genes in African and non‐African populations. American Journal of Human Genetics, 93(3), 545–554. doi: 10.1016/j.ajhg.2013.07.010.
  Freedman, M. L., Reich, D., Penney, K. L., McDonald, G. J., Mignault, A. A., Patterson, N., … Altshuler, D. (2004). Assessing the impact of population stratification on genetic association studies. Nature Genetics, 36(4), 388–393. doi: 10.1038/ng1333.
  Friedrich, D. C., Santos, S. E., Ribeiro‐dos‐Santos, A. K., & Hutz, M. H. (2012). Several different lactase persistence associated alleles and high diversity of the lactase gene in the admixed Brazilian population. PLoS One, 7(9), e46520. doi: 10.1371/journal.pone.0046520.
  Galinsky, K. J., Bhatia, G., Loh, P. R., Georgiev, S., Mukherjee, S., Patterson, N. J., & Price, A. L. (2016). Fast principal‐component analysis reveals convergent evolution of ADH1B in Europe and East Asia. American Journal of Human Genetics, 98(3), 456–472. doi: 10.1016/j.ajhg.2015.12.022.
  Galvan, A., Vorraro, F., Cabrera, W., Ribeiro, O. G., Starobinas, N., Jensen, J. R., … Dragani, T. A. (2011). Association study by genetic clustering detects multiple inflammatory response loci in non‐inbred mice. Genes and Immunity, 12(5), 390–394. doi: 10.1038/gene.2011.10.
  Gao, X. & Martin, E. R. (2009). Using allele sharing distance for detecting human population stratification. Human Heredity, 68(3), 182–191. doi: 10.1159/000224638.
  Gao, X. & Starmer, J. (2007). Human population structure detection via multilocus genotype clustering. BMC Genetics [Electronic Resource], 8, 34. doi: 10.1186/1471‐2156‐8‐34.
  1000 Genomes Project Consortium, Abecasis, G. R., Auton, A., Brooks, L. D., DePristo, M. A., Durbin, R. M., … McVean, G. A. (2012). An integrated map of genetic variation from 1,092 human genomes. Nature, 491(7422), 56–65. doi: 10.1038/nature11632.
  Goddard, K. A., Hopkins, P. J., Hall, J. M., & Witte, J. S. (2000). Linkage disequilibrium and allele‐frequency distributions for 114 single‐nucleotide polymorphisms in five populations. American Journal of Human Genetics, 66(1), 216–234. doi: 10.1086/302727.
  Gomes, K. F., Santos, A. S., Semzezem, C., Correia, M. R., Brito, L. A., Ruiz, M. O., … Silva, M. E. (2017). The influence of population stratification on genetic markers associated with type 1 diabetes. Scientific Reports, 7, 43513. doi: 10.1038/srep43513.
  Gravel, S., Henn, B. M., Gutenkunst, R. N., Indap, A. R., Marth, G. T., Clark, A. G., … Bustamante, C. D. (2011). Demographic history and rare allele sharing among human populations. Proceedings of the National Academy of Sciences of the United States of America, 108(29), 11983–11988. doi: 10.1073/pnas.1019276108.
  Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., … Pääbo, S. (2010). A draft sequence of the Neandertal genome. Science, 328(5979), 710–722. doi: 10.1126/science.1188021.
  Harris, K., & Nielsen, R. (2013). Inferring demographic history from a spectrum of shared haplotype lengths. PLoS Genetics, 9(6), e1003521. doi: 10.1371/journal.pgen.1003521.
  Hartl, D. L., & Clark, A. G. (2007). Principles of population genetics, 4th ed. Sinauer Associates, Inc., Sunderland, MA.
  Higasa, K., Miyake, N., Yoshimura, J., Okamura, K., Niihori, T., Saitsu, H., … Matsuda, F. (2016). Human genetic variation database, a reference database of genetic variations in the Japanese population. Journal of Human Genetics, 61(6), 547–553. doi: 10.1038/jhg.2016.12.
  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. doi: 10.1086/375613.
  Hoggart, C. J., Shriver, M. D., Kittles, R. A., Clayton, D. G., & McKeigue, P. M. (2004). Design and analysis of admixture mapping studies. American Journal of Human Genetics, 74(5), 965–978. doi: 10.1086/420855.
  Holsinger, K. E., & Weir, B. S. (2009). Genetics in geographically structured populations: Defining, estimating and interpreting F(ST). Nature Reviews Genetics, 10(9), 639–650. doi: 10.1038/nrg2611.
  Homa, D. M., Mannino, D. M., & Lara, M. (2000). Asthma mortality in U.S. Hispanics of Mexican, Puerto Rican, and Cuban heritage, 1990‐1995. American Journal of Respiratory and Critical Care Medicine, 161(2 Pt 1), 504–509. doi: 10.1164/ajrccm.161.2.9906025.
  Huang, J., Howie, B., McCarthy, S., Memari, Y., Walter, K., Min, J. L., … Soranzo, N. (2015). Improved imputation of low‐frequency and rare variants using the UK10K haplotype reference panel. Nature Communications, 6, 8111. doi: 10.1038/ncomms9111.
  Ingram, C. J., Elamin, M. F., Mulcare, C. A., Weale, M. E., Tarekegn, A., Raga, T. O., … Swallow, D. M. (2007). A novel polymorphism associated with lactose tolerance in Africa: Multiple causes for lactase persistence? Human Genetics, 120(6), 779–788. doi: 10.1007/s00439‐006‐0291‐1.
  Ingram, C. J., Raga, T. O., Tarekegn, A., Browning, S. L., Elamin, M. F., Bekele, E., … Swallow, D. M. (2009). Multiple rare variants as a cause of a common phenotype: Several different lactase persistence associated alleles in a single ethnic group. Journal of Molecular Evolution, 69(6), 579–588. doi: 10.1007/s00239‐009‐9301‐y.
  Jenkins, D. L., Davis, L. G., Stafford, T. W., Jr., Campos, P. F., Hockett, B., Jones, G. T., … Willerslev, E. (2012). Clovis age Western Stemmed projectile points and human coprolites at the Paisley Caves. Science, 337(6091), 223–228. doi: 10.1126/science.1218443.
  Johnson, N. A., Coram, M. A., Shriver, M. D., Romieu, I., Barsh, G. S., London, S. J., & Tang, H. (2011). Ancestral components of admixed genomes in a Mexican cohort. PLoS Genetics, 7(12), e1002410. doi: 10.1371/journal.pgen.1002410.
  Kang, H. M., Sul, J. H., Service, S. K., Zaitlen, N. A., Kong, S. Y., Freimer, N. B., … Eskin, E. (2010). Variance component model to account for sample structure in genome‐wide association studies. Nature Genetics, 42(4), 348–354. doi: 10.1038/ng.548.
  Kang, H. M., Zaitlen, N. A., Wade, C. M., Kirby, A., Heckerman, D., Daly, M. J., & Eskin, E. (2008). Efficient control of population structure in model organism association mapping. Genetics, 178(3), 1709–1723. doi: 10.1534/genetics.107.080101.
  Kawai, Y., Mimori, T., Kojima, K., Nariai, N., Danjoh, I., Saito, R., … Nagasaki, M. (2015). Japonica array: Improved genotype imputation by designing a population‐specific SNP array with 1070 Japanese individuals. Journal of Human Genetics, 60(10), 581–587. doi: 10.1038/jhg.2015.68.
  Kim, K., Bang, S. Y., Lee, H. S., & Bae, S. C. (2014). Construction and application of a Korean reference panel for imputing classical alleles and amino acids of human leukocyte antigen genes. PLoS One, 9(11), e112546. doi: 10.1371/journal.pone.0112546.
  Knowler, W. C., Williams, R. C., Pettitt, D. J., & Steinberg, A. G. (1988). Gm3;5,13,14 and type 2 diabetes mellitus: An association in American Indians with genetic admixture. American Journal of Human Genetics, 43(4), 520–526.
  Kodaman, N., Aldrich, M. C., Smith, J. R., Signorello, L. B., Bradley, K., Breyer, J., … Williams, S. M. (2013). A small number of candidate gene SNPs reveal continental ancestry in African Americans. Annals of Human Genetics, 77(1), 56–66.doi: 10.1111/j.1469‐1809.2012.00738.x.
  Kohler, K. & Bickeboller, H. (2006). Case‐control association tests correcting for population stratification. Annals of Human Genetics, 70(Pt 1), 98–115. doi: 10.1111/j.1529‐8817.2005.00214.x.
  Lappalainen, T., Salmela, E., Andersen, P. M., Dahlman‐Wright, K., Sistonen, P., Savontaus, M. L., … Kere, J. (2010). Genomic landscape of positive natural selection in Northern European populations. European Journal of Human Genetics, 18(4), 471–478. doi: 10.1038/ejhg.2009.184.
  Lee, S. H., Wray, N. R., Goddard, M. E., & Visscher, P. M. (2011). Estimating missing heritability for disease from genome‐wide association studies. American Journal of Human Genetics, 88(3), 294–305. doi: 10.1016/j.ajhg.2011.02.002.
  Lewinsky, R. H., Jensen, T. G., Moller, J., Stensballe, A., Olsen, J., & Troelsen, J. T. (2005). T‐13910 DNA variant associated with lactase persistence interacts with Oct‐1 and stimulates lactase promoter activity in vitro. Human Molecular Genetics, 14(24), 3945–3953. doi: 10.1093/hmg/ddi418.
  Li, H. & Durbin, R. (2011). Inference of human population history from individual whole‐genome sequences. Nature, 475(7357), 493–496. doi: 10.1038/nature10231.
  Li, N. & Stephens, M. (2003). Modeling linkage disequilibrium and identifying recombination hotspots using single‐nucleotide polymorphism data. Genetics, 165, 2213–2233.
  Listgarten, J., Lippert, C., Kadie, C. M., Davidson, R. I., Eskin, E., & Heckerman, D. (2012). Improved linear mixed models for genome‐wide association studies. Nature Methods, 9(6), 525–526. doi: 10.1038/nmeth.2037.
  Low‐Kam, C., Rhainds, D., Lo, K. S., Provost, S., Mongrain, I., Dubois, A., … Lettre, G. (2016). Whole‐genome sequencing in French Canadians from Quebec. Human Genetics, 135(11), 1213–1221. doi: 10.1007/s00439‐016‐1702‐6.
  Mallick, S., Li, H., Lipson, M., Mathieson, I., Gymrek, M., Racimo, F., … Reich, D. (2016). The Simons Genome Diversity Project: 300 genomes from 142 diverse populations. Nature, 538(7624), 201–206. doi: 10.1038/nature18964.
  Maples, B. K., Gravel, S., Kenny, E. E., & Bustamante, C. D. (2013). RFMix: A discriminative modeling approach for rapid and robust local‐ancestry inference. American Journal of Human Genetics, 93, 278–288. doi: 10.1016/j.ajhg.2013.06.020.
  Marcheco‐Teruel, B., Parra, E. J., Fuentes‐Smith, E., Salas, A., Buttenschon, H. N., Demontis, D., … Mors, O. (2014). Cuba: Exploring the history of admixture and the genetic basis of pigmentation using autosomal and uniparental markers. PLoS Genetics, 10(7), e1004488. doi: 10.1371/journal.pgen.1004488.
  Marchini, J., Cardon, L. R., Phillips, M. S., & Donnelly, P. (2004). The effects of human population structure on large genetic association studies. Nature Genetics, 36(5), 512–517. doi: 10.1038/ng1337.
  Martin, L. S. & Eskin, E. (2017). Review: Population structure in genetic studies: Confounding factors and mixed models. bioRxiv, https://doi.org/10.1101/092106.
  McCarthy, S., Das, S., Kretzschmar, W., Delaneau, O., Wood, A. R., Teumer, A., … Haplotype Reference Consortium (2016). A reference panel of 64,976 haplotypes for genotype imputation. Nature Genetics, 48(10), 1279–1283. doi: 10.1038/ng.3643.
  McDougall, I., Brown, F. H., & Fleagle, J. G. (2005). Stratigraphic placement and age of modern humans from Kibish, Ethiopia. Nature, 433(7027), 733–736. doi: 10.1038/nature03258.
  McKeigue, P. M. (1998). Mapping genes that underlie ethnic differences in disease risk: Methods for detecting linkage in admixed populations, by conditioning on parental admixture. American Journal of Human Genetics, 63, 241–251. doi: 10.1086/301908.
  Mendizabal, I., Sandoval, K., Berniell‐Lee, G., Calafell, F., Salas, A., Martinez‐Fuentes, A., & Comas, D. (2008). Genetic origin, admixture, and asymmetry in maternal and paternal human lineages in Cuba. BMC Evolutionary Biology [Electronic Resource], 8, 213. doi: 10.1186/1471‐2148‐8‐213.
  Meyer, M., Kircher, M., Gansauge, M. T., Li, H., Racimo, F., Mallick, S., … Pääbo, S. (2012). A high‐coverage genome sequence from an archaic Denisovan individual. Science, 338(6104), 222–226. doi: 10.1126/science.1224344.
  Miclaus, K., Wolfinger, R., & Czika, W. (2009). SNP selection and multidimensional scaling to quantify population structure. Genetic Epidemiology, 33(6), 488–496. doi: 10.1002/gepi.20401.
  Monda, K. L., Chen, G. K., Taylor, K. C., Palmer, C., Edwards, T. L., Lange, L. A., … Haiman, C. A. (2013). A meta‐analysis identifies new loci associated with body mass index in individuals of African ancestry. Nature Genetics, 45(6), 690–696. doi: 10.1038/ng.2608.
  Montana, G. & Hoggart, C. (2007). Statistical software for gene mapping by admixture linkage disequilibrium. Briefings in Bioinformatics, 8(6), 393–395. doi: 10.1093/bib/bbm035.
  Montana, G. & Pritchard, J. K. (2004). Statistical tests for admixture mapping with case‐control and cases‐only data. American Journal of Human Genetics, 75(5), 771–789. doi: 10.1086/425281.
  Moreno‐Estrada, A., Gravel, S., Zakharia, F., McCauley, J. L., Byrnes, J. K., Gignoux, C. R., … Bustamante, C. D. (2013). Reconstructing the population genetic history of the Caribbean. PLoS Genetics, 9(11), e1003925. doi: 10.1371/journal.pgen.1003925.
  Mulcare, C. A., Weale, M. E., Jones, A. L., Connell, B., Zeitlyn, D., Tarekegn, A., … Thomas, M. G. (2004). The T allele of a single‐nucleotide polymorphism 13.9 kb upstream of the lactase gene (LCT) (C‐13.9kbT) does not predict or cause the lactase‐persistence phenotype in Africans. American Journal of Human Genetics, 74(6), 1102–1110. doi: 10.1086/421050.
  Nielsen, R., Akey, J. M., Jakobsson, M., Pritchard, J. K., Tishkoff, S., & Willerslev, E. (2017). Tracing the peopling of the world through genomics. Nature, 541(7637), 302–310. doi: 10.1038/nature21347.
  Novembre, J., Johnson, T., Bryc, K., Kutalik, Z., Boyko, A. R., Auton, A., … Bustamante, C. D. (2008). Genes mirror geography within Europe. Nature, 456(7218), 98–101. doi: 10.1038/nature07331.
  Olds, L. C., & Sibley, E. (2003). Lactase persistence DNA variant enhances lactase promoter activity in vitro: Functional role as a cis regulatory element. Human Molecular Genetics, 12(18), 2333–2340. doi: 10.1093/hmg/ddg244.
  Ott, J., Wang, J., & Leal, S. M. (2015). Genetic linkage analysis in the age of whole‐genome sequencing. Nature Reviews Genetics, 16(5), 275–284. doi: 10.1038/nrg3908.
  Pasaniuc, B., Sankararaman, S., Kimmel, G., & Halperin, E. (2009). Inference of locus‐specific ancestry in closely related populations. Bioinformatics (Oxford, England), 25, i213–221. doi: 10.1093/bioinformatics/btp197.
  Pasaniuc, B., Zaitlen, N., Lettre, G., Chen, G. K., Tandon, A., Kao, W. H. L., … Price, A. L. (2011). Enhanced statistical tests for GWAS in admixed populations: Assessment using African Americans from CARe and a Breast Cancer Consortium. PLoS Genetics, 7, e1001371. doi: 10.1371/journal.pgen.1001371.
  Patterson, N., Hattangadi, N., Lane, B., Lohmueller, K. E., Hafler, D. A., Oksenberg, J. R., … Reich, D. (2004). Methods for high‐density admixture mapping of disease genes. American Journal of Human Genetics, 74(5), 979–1000. doi: 10.1086/420871.
  Pena, S. D., Di Pietro, G., Fuchshuber‐Moraes, M., Genro, J. P., Hutz, M. H., Kehdy Fde, S., … Suarez‐Kurtz, G. (2011). The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS One, 6(2), e17063. doi: 10.1371/journal.pone.0017063.
  Price, A. L., Patterson, N. J., Plenge, R. M., Weinblatt, M. E., Shadick, N. A., & Reich, D. (2006). Principal components analysis corrects for stratification in genome‐wide association studies. Nature Genetics, 38(8), 904–909. doi: 10.1038/ng1847.
  Price, A. L., Tandon, A., Patterson, N., Barnes, K. C., Rafaels, N., Ruczinski, I., … Myers, S. (2009). Sensitive detection of chromosomal segments of distinct ancestry in admixed populations. PLoS Genetics, 5, e1000519. doi: 10.1371/journal.pgen.1000519.
  Price, A. L., Zaitlen, N. A., Reich, D., & Patterson, N. (2010). New approaches to population stratification in genome‐wide association studies. Nature Reviews Genetics, 11(7), 459–463. doi: 10.1038/nrg2813.
  Pritchard, J. K., & Donnelly, P. (2001). Case‐control studies of association in structured or admixed populations. Theoretical Population Biology, 60(3), 227–237. doi: 10.1006/tpbi.2001.1543.
  Pritchard, J. K., Stephens, M., & Donnelly, P. (2000a). Inference of population structure using multilocus genotype data. Genetics, 155(2), 945–959.
  Pritchard, J. K., Stephens, M., Rosenberg, N. A., & Donnelly, P. (2000b). Association mapping in structured populations. American Journal of Human Genetics, 67(1), 170–181. doi: 10.1086/302959.
  Purcell, S., Neale, B., Todd‐Brown, K., Thomas, L., Ferreira, M. A., Bender, D., … Sham, P. C. (2007). PLINK: A tool set for whole‐genome association and population‐based linkage analyses. American Journal of Human Genetics, 81(3), 559–575. doi: 10.1086/519795.
  Rosenberg, N. A., Pritchard, J. K., Weber, J. L., Cann, H. M., Kidd, K. K., Zhivotovsky, L. A., & Feldman, M. W. (2002). Genetic structure of human populations. Science, 298(5602), 2381–2385. doi: 10.1126/science.1078311.
  Ruiz‐Narvaez, E. A., Rosenberg, L., Wise, L. A., Reich, D., & Palmer, J. R. (2011). Validation of a small set of ancestral informative markers for control of population admixture in African Americans. American Journal of Epidemiology, 173(5), 587–592. doi: 10.1093/aje/kwq401.
  Sankararaman, S., Sridhar, S., Kimmel, G., & Halperin, E. (2008). Estimating local ancestry in admixed populations. American Journal of Human Genetics, 82, 290–303. doi: 10.1016/j.ajhg.2007.09.022.
  Schanfield, M. S. & Kirk, R. L. (1981). Further studies on the immunoglobulin allotypes (Gm, Am and Km) in India. Acta Anthropogenetica, 5(1), 1–21.
  Schlebusch, C. M., Skoglund, P., Sjodin, P., Gattepaille, L. M., Hernandez, D., Jay, F., … Jakobsson, M. (2012). Genomic variation in seven Khoe‐San groups reveals adaptation and complex African history. Science, 338(6105), 374–379. doi: 10.1126/science.1227721.
  Seldin, M. F., Pasaniuc, B., & Price, A. L. (2011). New approaches to disease mapping in admixed populations. Nature Reviews Genetics, 12, 523–528. doi: 10.1038/nrg3002.
  Shriner, D. (2017). Overview of admixture mapping. Current Protocols in Human Genetics, 94, 1.23.1–1.23.8. doi: 10.1002/cphg.44
  Shriner, D., Adeyemo, A., & Rotimi, C. N. (2011). Joint ancestry and association testing in admixed individuals. PLoS Computational Biology, 7, e1002325. doi: 10.1371/journal.pcbi.1002325.
  Silva, M. E., Mory, D., & Davini, E. (2008). [Genetic and humoral autoimmunity markers of type 1 diabetes: From theory to practice]. Arquivos Brasileiros De Endocrinologia E Metabologia, 52(2), 166–180. doi: 10.1590/S0004‐27302008000200004.
  Skotte, L., Korneliussen, T. S., & Albrechtsen, A. (2013). Estimating individual admixture proportions from next generation sequencing data. Genetics, 195(3), 693–702. doi: 10.1534/genetics.113.154138.
  Spielman, R. S., Baur, M. P., & Clerget‐Darpoux, F. (1989). Genetic analysis of IDDM: Summary of GAW5 IDDM results. Genetic Epidemiology, 6(1), 43–58. doi: 10.1002/gepi.1370060111.
  Spielman, R. S., McGinnis, R. E., & Ewens, W. J. (1993). Transmission test for linkage disequilibrium: The insulin gene region and insulin‐dependent diabetes mellitus (IDDM). American Journal of Human Genetics, 52(3), 506–516.
  Steele, C. D., Court, D. S., & Balding, D. J. (2014). Worldwide F(ST) estimates relative to five continental‐scale populations. Annals of Human Genetics, 78(6), 468–477. doi: 10.1111/ahg.12081.
  Sundquist, A., Fratkin, E., Do, C. B., & Batzoglou, S. (2008). Effect of genetic divergence in identifying ancestral origin using HAPAA. Genome Research, 18, 676–682. doi: 10.1101/gr.072850.107.
  Taliun, D., Chothani, S. P., Schonherr, S., Forer, L., Boehnke, M., Abecasis, G. R., & Wang, C. (2017). LASER server: Ancestry tracing with genotypes or sequence reads. Bioinformatics (Oxford, England), 33(13), 2056–2058. doi: 10.1093/bioinformatics/btx075.
  Tang, D., Anderson, D., Francis, R. W., Syn, G., Jamieson, S. E., Lassmann, T., & Blackwell, J. M. (2016). Reference genotype and exome data from an Australian Aboriginal population for health‐based research. Scientific Data, 3, 160023. doi: 10.1038/sdata.2016.23.
  Tang, H., Coram, M., Wang, P., Zhu, X., & Risch, N. (2006). Reconstructing genetic ancestry blocks in admixed individuals. American Journal of Human Genetics, 79(1), 1–12. doi: 10.1086/504302.
  Teare, M. D. & Santibanez Koref, M. F. (2014). Linkage analysis and the study of Mendelian disease in the era of whole exome and genome sequencing. Briefings in Functional Genomics, 13(5), 378–383. doi: 10.1093/bfgp/elu024.
  Thareja, G., John, S. E., Hebbar, P., Behbehani, K., Thanaraj, T. A., & Alsmadi, O. (2015). Sequence and analysis of a whole genome from Kuwaiti population subgroup of Persian ancestry. BMC Genomics [Electronic Resource], 16, 92. doi: 10.1186/s12864‐015‐1233‐x.
  Thomson, G., Valdes, A. M., Noble, J. A., Kockum, I., Grote, M. N., Najman, J., … Nerup, J. (2007). Relative predispositional effects of HLA class II DRB1‐DQB1 haplotypes and genotypes on type 1 diabetes: A meta‐analysis. Tissue Antigens, 70(2), 110–127. doi: 10.1111/j.1399‐0039.2007.00867.x.
  Thornton, T., & McPeek, M. S. (2010). ROADTRIPS: Case‐control association testing with partially or completely unknown population and pedigree structure. American Journal of Human Genetics, 86(2), 172–184. doi: 10.1016/j.ajhg.2010.01.001.
  Tishkoff, S. A., Reed, F. A., Friedlaender, F. R., Ehret, C., Ranciaro, A., Froment, A., … Williams, S. M. (2009). The genetic structure and history of Africans and African Americans. Science, 324(5930), 1035–1044. doi: 10.1126/science.1172257.
  Tishkoff, S. A., Reed, F. A., Ranciaro, A., Voight, B. F., Babbitt, C. C., Silverman, J. S., … Deloukas, P. (2007). Convergent adaptation of human lactase persistence in Africa and Europe. Nature Genetics, 39(1), 31–40. doi: 10.1038/ng1946.
  Tung, J. Y., Do, C. B., Hinds, D. A., Kiefer, A. K., Macpherson, J. M., Chowdry, A. B., … Eriksson, N. (2011). Efficient replication of over 180 genetic associations with self‐reported medical data. PLoS One, 6(8), e23473. doi: 10.1371/journal.pone.0023473.
  Velez, D. R., Fortunato, S. J., Thorsen, P., Lombardi, S. J., Williams, S. M., & Menon, R. (2008). Preterm birth in Caucasians is associated with coagulation and inflammation pathway gene variants. PLoS One, 3(9), e3283. doi: 10.1371/journal.pone.0003283.
  Vernot, B. & Akey, J. M. (2015). Complex history of admixture between modern humans and Neandertals. American Journal of Human Genetics, 96(3), 448–453. doi: 10.1016/j.ajhg.2015.01.006.
  Vigilant, L., Stoneking, M., Harpending, H., Hawkes, K., & Wilson, A. C. (1991). African populations and the evolution of human mitochondrial DNA. Science, 253(5027), 1503–1507. doi: 10.1126/science.1840702.
  Voight, B. F. & Pritchard, J. K. (2005). Confounding from cryptic relatedness in case‐control association studies. PLoS Genetics, 1(3), e32. doi: 10.1371/journal.pgen.0010032.
  Wahlund, S. (1928). Composition of populations from the perspective of the theory of heredity. Hereditas, 11, 65–105. doi: 10.1111/j.1601‐5223.1928.tb02483.x.
  Wang, S., Chen, W., Chen, X., Hu, F., Archer, K. J., Liu, H. N., … Gao, G. (2012a). Double genomic control is not effective to correct for population stratification in meta‐analysis for genome‐wide association studies. Front Genet, 3, 300. doi: 10.3389/fgene.2012.00300.
  Wang, K., Hu, X., & Peng, Y. (2013). An analytical comparison of the principal component method and the mixed effects model for association studies in the presence of cryptic relatedness and population stratification. Human Heredity, 76(1), 1–9. doi: 10.1159/000353345.
  Wang, C., Zhan, X., Bragg‐Gresham, J., Kang, H. M., Stambolian, D., Chew, E. Y., … Abecasis, G. R. (2014). Ancestry estimation and control of population stratification for sequence‐based association studies. Nature Genetics, 46(4), 409–415. doi: 10.1038/ng.2924.
  Wang, C., Zhan, X., Liang, L., Abecasis, G. R., & Lin, X. (2015). Improved ancestry estimation for both genotyping and sequencing data using projection procrustes analysis and genotype imputation. American Journal of Human Genetics, 96(6), 926–937. doi: 10.1016/j.ajhg.2015.04.018.
  Wang, X., Zhu, X., Qin, H., Cooper, R. S., Ewens, W. J., Li, C., & Li, M. (2011). Adjustment for local ancestry in genetic association analysis of admixed populations. Bioinformatics (Oxford, England), 27(5), 670–677. doi: 10.1093/bioinformatics/btq709.
  Wang, C., Zollner, S., & Rosenberg, N. A. (2012b). A quantitative comparison of the similarity between genes and geography in worldwide human populations. PLoS Genetics, 8(8), e1002886. doi: 10.1371/journal.pgen.1002886.
  Weir, B. S., & Cockerham, C. C. (1984). Estimating F‐statistics for the analysis of population structure. Evolution, 38(6), 1358–1370.
  Weir, B. S. & Hill, W. G. (2002). Estimating F‐statistics. Annual Review of Genetics, 36, 721–750. doi: 10.1146/annurev.genet.36.050802.093940.
  White, T. D., Asfaw, B., DeGusta, D., Gilbert, H., Richards, G. D., Suwa, G., & Howell, F. C. (2003). Pleistocene Homo sapiens from Middle Awash, Ethiopia. Nature, 423(6941), 742–747. doi: 10.1038/nature01669.
  Williams, R. C., Steinberg, A. G., Gershowitz, H., Bennett, P. H., Knowler, W. C., Pettitt, D. J., … Smith, C. G. (1985). GM allotypes in Native Americans: Evidence for three distinct migrations across the Bering land bridge. American Journal of Physical Anthropology, 66(1), 1–19. doi: 10.1002/ajpa.1330660102.
  Winkler, C. A., Nelson, G. W., & Smith, M. W. (2010). Admixture mapping comes of age. Annual Review of Genomics and Human Genetics, 11, 65–89. doi: 10.1146/annurev‐genom‐082509‐141523.
  Wong, L. P., Lai, J. K., Saw, W. Y., Ong, R. T., Cheng, A. Y., Pillai, N. E., … Teo, Y. Y. (2014). Insights into the genetic structure and diversity of 38 South Asian Indians from deep whole‐genome sequencing. PLoS Genetics, 10(5), e1004377. doi: 10.1371/journal.pgen.1004377.
  Wong, L. P., Ong, R. T., Poh, W. T., Liu, X., Chen, P., Li, R., … Teo, Y. Y. (2013). Deep whole‐genome sequencing of 100 southeast Asian Malays. American Journal of Human Genetics, 92(1), 52–66. doi: 10.1016/j.ajhg.2012.12.005.
  Wright, S. (1921). Systems of mating. V. General considerations. Genetics, 6(2), 167–178.
  Yang, B. Z., Zhao, H., Kranzler, H. R., & Gelernter, J. (2005). Practical population group assignment with selected informative markers: Characteristics and properties of Bayesian clustering via STRUCTURE. Genetic Epidemiology, 28(4), 302–312. doi: 10.1002/gepi.20070.
  Yang, J., Benyamin, B., McEvoy, B. P., Gordon, S., Henders, A. K., Nyholt, D. R., … Visscher, P. M. (2010). Common SNPs explain a large proportion of the heritability for human height. Nature Genetics, 42(7), 565–569. doi: 10.1038/ng.608.
  Yang, J., Lee, S. H., Goddard, M. E., & Visscher, P. M. (2011). GCTA: A tool for genome‐wide complex trait analysis. American Journal of Human Genetics, 88(1), 76–82. doi: 10.1016/j.ajhg.2010.11.011.
  Yang, W. Y., Novembre, J., Eskin, E., & Halperin, E. (2012). A model‐based approach for analysis of spatial structure in genetic data. Nature Genetics, 44(6), 725–731. doi: 10.1038/ng.2285.
  Zhang, F., Wang, Y., & Deng, H. W. (2008). Comparison of population‐based association study methods correcting for population stratification. PLoS One, 3(10), e3392. doi: 10.1371/journal.pone.0003392.
  Zhou, X. & Stephens, M. (2012). Genome‐wide efficient mixed‐model analysis for association studies. Nature Genetics, 44(7), 821–824. doi: 10.1038/ng.2310.
  Zhu, X., Li, S., Cooper, R. S., & Elston, R. C. (2008). A unified association analysis approach for family and unrelated samples correcting for stratification. American Journal of Human Genetics, 82(2), 352–365. doi: 10.1016/j.ajhg.2007.10.009.
  Zhu, X., Zhang, S., Tang, H., & Cooper, R. (2006). A classical likelihood based approach for admixture mapping using EM algorithm. Human Genetics, 120(3), 431–445. doi: 10.1007/s00439‐006‐0224‐z.
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