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Admixture-matched case-control study: a practical approach for genetic association studies in admixed populations

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Abstract

Case-control genetic association studies in admixed populations are known to be susceptible to genetic confounding due to population stratification. The transmission/disequilibrium test (TDT) approach can avoid this problem. However, the TDT is expensive and impractical for late-onset diseases. Case-control study designs, in which, cases and controls are matched by admixture, can be an appealing and a suitable alternative for genetic association studies in admixed populations. In this study, we applied this matching strategy when recruiting our African American participants in the Study of African American, Asthma, Genes and Environments. Group admixture in this cohort consists of 83% African ancestry and 17% European ancestry, which was consistent with reports from other studies. By carrying out several complementary analyses, our results show that there is a substructure in the cohort, but that the admixture distributions are almost identical in cases and controls, and also in cases only. We performed association tests for asthma-related traits with ancestry, and only found that FEV1, a measure for baseline pulmonary function, was associated with ancestry after adjusting for socio-economic and environmental risk factors (P=0.01). We did not observe an excess of type I error rate in our association tests for ancestry informative markers and asthma-related phenotypes when ancestry was not adjusted in the analyses. Furthermore, using the association tests between genetic variants in a known asthma candidate gene, β2 adrenergic receptor (β2AR) and ΔFEF25–75, an asthma-related phenotype, as an example, we demonstrated population stratification was not a confounder in our genetic association. Our present work demonstrates that admixture-matched case-control strategies can efficiently control population stratification confounding in admixed populations.

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References

  • Abecasis GR, Cardon LR, Cookson WO (2000) A general test of association for quantitative traits in nuclear families. Am J Hum Genet 66:279–292

    Article  PubMed  CAS  Google Scholar 

  • Akey JM, Zhang G, Zhang K, Jin L, Shriver MD (2002) Interrogating a high-density SNP map for signatures of natural selection. Genome Res 12:1805–1814

    Article  PubMed  CAS  Google Scholar 

  • Akinbami LJ, Rhodes JC, Lara M (2005) Racial and ethnic differences in asthma diagnosis among children who wheeze. Pediatrics 115:1254–1260

    Article  PubMed  Google Scholar 

  • Akinbami LJ, Schoendorf KC (2002) Trends in childhood asthma: prevalence, health care utilization, and mortality. Pediatrics 110:315–322

    Article  PubMed  Google Scholar 

  • Allison DB (1997) Transmission-disequilibrium tests for quantitative traits. Am J Hum Genet 60:676–690

    PubMed  CAS  Google Scholar 

  • Bacanu SA, Devlin B, Roeder K (2000) The power of genomic control. Am J Hum Genet 66:1933–1944

    Article  PubMed  CAS  Google Scholar 

  • Bertorelle G, Excoffier L (1998) Inferring admixture proportions from molecular data. Mol Biol Evol 15:1298–1311

    PubMed  CAS  Google Scholar 

  • Bonilla C, Parra EJ, Pfaff CL, Dios S, Marshall JA, Hamman RF, Ferrell RE, Hoggart CL, McKeigue PM, Shriver MD (2004) Admixture in the Hispanics of the San Luis Valley, Colorado, and its implications for complex trait gene mapping. Ann Hum Genet 68:139–153

    Article  PubMed  CAS  Google Scholar 

  • Burchard EG, Avila PC, Nazario S, Casal J, Torres A, Rodriguez-Santana JR, Sylvia JS, Fagan JK, Salas J, Lilly CM, Ziv E, Selman M, Chapela R, Sheppard D, Weiss ST, Ford JG, Boushey HA, Rodriguez-Cintron W, Drazen JM, Silverman EK (2003a) Lower bronchodilator responsiveness in Puerto Rican than in Mexican asthmatic subjects. Am J Respir Crit Care Med 169(3):386–392

    Article  PubMed  Google Scholar 

  • Burchard EG, Ziv E, Coyle N, Gomez SL, Tang H, Karter AJ, Mountain JL, Perez-Stable EJ, Sheppard D, Risch N (2003b) The importance of race and ethnic background in biomedical research and clinical practice. N Engl J Med 348:1170–1175

    Article  PubMed  Google Scholar 

  • Cardon LR, Bell JI (2001) Association study designs for complex diseases. Nat Rev Genet 2:91–99

    Article  PubMed  CAS  Google Scholar 

  • Cardon LR, Palmer LJ (2003) Population stratification and spurious allelic association. Lancet 361:598–604

    Article  PubMed  Google Scholar 

  • Chen X, Kwok PY (1999) Homogeneous genotyping assays for single nucleotide polymorphisms with fluorescence resonance energy transfer detection. Genet Anal 14:157–163

    PubMed  CAS  Google Scholar 

  • Choudhry S, Ung N, Avila PC, Ziv E, Nazario S, Casal J, Torres A, Gorman JD, Salari K, Rodriguez-Santana JR, Toscano M, Sylvia JS, Alioto M, Castro RA, Salazar M, Gomez I, Fagan JK, Salas J, Clark S, Lilly C, Matallana H, Selman M, Chapela R, Sheppard D, Weiss ST, Ford JG, Boushey HA, Drazen JM, Rodriguez-Cintron W, Silverman EK, Burchard EG (2005) Pharmacogenetic differences in response to albuterol between Puerto Ricans and Mexicans with asthma. Am J Respir Crit Care Med 171:563–570

    Article  PubMed  Google Scholar 

  • Choudhry S, Coyle NE, Tang H, Salari K, Lind D, Clark SL, Tsai HJ, Naqvi M, Phong A, Ung N, Matallana H, Avila PC, Casal J, Torres A, Nazario S, Castro R, Battle NC, Perez-Stable EJ, Kwok PY, Sheppard D, Shriver MD, Rodriguez-Cintron W, Risch N, Ziv E, Burchard EG (2005) Population Stratification Confounds Genetic Association Studies of Asthma among Latino Americans. Hum Genet (in press)

  • Devlin B, Roeder K, Wasserman L (2001) Genomic control, a new approach to genetic-based association studies. Theoretical Population Biology 60:155–166

    Article  PubMed  CAS  Google Scholar 

  • Dupanloup I, Bertorelle G (2001) Inferring admixture proportions from molecular data: extension to any number of parental populations. Mol Biol Evol 18:672–675

    PubMed  CAS  Google Scholar 

  • Enright PL, Johnson LR, Connett JE, Voelker H, Buist AS (1991) Spirometry in the Lung Health Study. 1. Methods and quality control. Am Rev Respir Dis 143:1215–1223

    PubMed  CAS  Google Scholar 

  • Enright PL, Lebowitz MD, Cockroft DW (1994) Physiologic measures: pulmonary function tests. Asthma outcome. Am J Respir Crit Care Med 149: S9–18; discussion S19–20

  • Evans DA, McLeod HL, Pritchard S, Tariq M, Mobarek A (2001) Interethnic variability in human drug responses. Drug Metab Dispos 29:606–610

    PubMed  Google Scholar 

  • Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927

    PubMed  CAS  Google Scholar 

  • Falush D, Stephens M, Pritchard JK (2003) Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 164:1567–1587

    PubMed  CAS  Google Scholar 

  • Freedman ML, Reich D, Penney KL, McDonald GJ, Mignault AA, Patterson N, Gabriel SB, Topol EJ, Smoller JW, Pato CN, Pato MT, Petryshen TL, Kolonel LN, Lander ES, Sklar P, Henderson B, Hirschhorn JN, Altshuler D (2004) Assessing the impact of population stratification on genetic association studies. Nat Genet 36:388–393

    Article  PubMed  CAS  Google Scholar 

  • Fuhlbrigge AL, Kitch BT, Paltiel AD, Kuntz KM, Neumann PJ, Dockery DW, Weiss ST (2001) FEV(1) is associated with risk of asthma attacks in a pediatric population. J Allergy Clin Immunol 107:61–67

    Article  PubMed  CAS  Google Scholar 

  • Glass B, Li CC (1953) The dynamics of racial intermixture; an analysis based on the American Negro. Am J Hum Genet 5:1–20

    PubMed  CAS  Google Scholar 

  • Hankinson JL, Odencrantz JR, Fedan KB (1999) Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med 159:179–187

    PubMed  CAS  Google Scholar 

  • Hinds DA, Stokowski RP, Patil N, Konvicka K, Kershenobich D, Cox DR, Ballinger DG (2004) Matching strategies for genetic association studies in structured populations. Am J Hum Genet 74:317–325

    Article  PubMed  CAS  Google Scholar 

  • Hogg JC, Macklem PT, Thurlbeck WM (1968) Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med 278:1355–1360

    Article  PubMed  CAS  Google Scholar 

  • Hoggart CJ, Parra EJ, Shriver MD, Bonilla C, Kittles RA, Clayton DG, McKeigue PM (2003) Control of confounding of genetic associations in stratified populations. Am J Hum Genet 72:1492–1504

    Article  PubMed  CAS  Google Scholar 

  • Holloway JW, Dunbar PR, Riley GA, Sawyer GM, Fitzharris PF, Pearce N, Le Gros GS, Beasley R (2000) Association of beta2-adrenergic receptor polymorphisms with severe asthma. Clin Exp Allergy 30:1097–1103

    Article  PubMed  CAS  Google Scholar 

  • Kitch BT, Paltiel AD, Kuntz KM, Dockery DW, Schouten JP, Weiss ST, Fuhlbrigge AL (2004) A single measure of FEV1 is associated with risk of asthma attacks in long-term follow-up. Chest 126:1875–1882

    Article  PubMed  Google Scholar 

  • Lander ES, Schork NJ (1994) Genetic dissection of complex traits. Science 265:2037–2048

    Article  PubMed  CAS  Google Scholar 

  • Lin CC, Rogot E, Johnson NJ, Sorlie PD, Arias E (2003) A further study of life expectancy by socioeconomic factors in the National Longitudinal Mortality Study. Ethn Dis 13:240–247

    PubMed  Google Scholar 

  • Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC (2002) Surveillance for asthma–United States, 1980–1999. MMWR Surveill Summ 51: 1–13

    Google Scholar 

  • Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R (1997) Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest 100:3184–3188

    Article  PubMed  CAS  Google Scholar 

  • Parra EJ, Marcini A, Akey J, Martinson J, Batzer MA, Cooper R, Forrester T, Allison DB, Deka R, Ferrell RE, Shriver MD (1998) Estimating African American admixture proportions by use of population-specific alleles. Am J Hum Genet 63:1839–1851

    Article  PubMed  CAS  Google Scholar 

  • Parra EJ, Hoggart CJ, Bonilla C, Dios S, Norris JM, Marshall JA, Hamman RF, Ferrell RE, McKeigue PM, Shriver MD (2004) Relation of type 2 diabetes to individual admixture and candidate gene polymorphisms in the Hispanic American population of San Luis Valley, Colorado. J Med Genet 41:e116

    Article  PubMed  CAS  Google Scholar 

  • Pearce N, Sunyer J, Cheng S, Chinn S, Bjorksten B, Burr M, Keil U, Anderson HR, Burney P (2000) Comparison of asthma prevalence in the ISAAC and the ECRHS. ISAAC Steering Committee and the European Community Respiratory Health Survey. International Study of Asthma and Allergies in Childhood. Eur Respir J 16:420–426

    Article  PubMed  CAS  Google Scholar 

  • Pfaff CL, Parra EJ, Bonilla C, Hiester K, McKeigue PM, Kamboh MI, Hutchinson RG, Ferrell RE, Boerwinkle E, Shriver MD (2001) Population structure in admixed populations: effect of admixture dynamics on the pattern of linkage disequilibrium. Am J Hum Genet 68:198–207

    Article  PubMed  CAS  Google Scholar 

  • Pritchard JK, Stephens M, Donnelly P (2000) Inference of population structure using multilocus genotype data. Genetics 155:945–959

    PubMed  CAS  Google Scholar 

  • Pritchard JK, Donnelly P (2001) Case-control studies of association in structured or admixed populations. Theor Popul Biol 60:227–237

    Article  PubMed  CAS  Google Scholar 

  • Reiner AP, Ziv E, Lind DL, Nievergelt CM, Schork NJ, Cummings SR, Phong A, Burchard EG, Harris TB, Psaty BM, Kwok PY (2005) Population structure, admixture, and aging-related phenotypes in African American adults: the Cardiovascular Health Study. Am J Hum Genet 76:463–477

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez MA, Winkleby MA, Ahn D, Sundquist J, Kraemer HC (2002) Identification of population subgroups of children and adolescents with high asthma prevalence: findings from the Third National Health and Nutrition Examination Survey. Arch Pediatr Adolesc Med 156:269–275

    PubMed  Google Scholar 

  • Romieu I, Mannino DM, Redd SC, McGeehin MA (2004) Dietary intake, physical activity, body mass index, and childhood asthma in the Third National Health And Nutrition Survey (NHANES III). Pediatr Pulmonol 38:31–42

    Article  PubMed  Google Scholar 

  • Salari K, Choudhry S, Tang H, Naqvi M, Lind D, Avila PC, Coyle NE, Ung N, Nazario S, Casal J, Torres-Palacios A, Clark S, Phong A, Gomez I, Matallana H, Perez-Stable EJ, Shriver MD, Kwok PY, Sheppard D, Rodriguez-Cintron W, Risch NJ, Burchard EG, Ziv E (2005) Genetic admixture and asthma-related phenotypes in Mexican American and Puerto Rican asthmatics. Genet Epidemiol 29:76–86

    Article  PubMed  Google Scholar 

  • Schlesselman JJ, Stolley PD (1982) Case control studies : design, conduct, analysis. Oxford University Press, New York

    Google Scholar 

  • Shriver MD, Parra EJ, Dios S, Bonilla C, Norton H, Jovel C, Pfaff C, Jones C, Massac A, Cameron N, Baron A, Jackson T, Argyropoulos G, Jin L, Hoggart CJ, McKeigue PM, Kittles RA (2003) Skin pigmentation, biogeographical ancestry and admixture mapping. Hum Genet 112:387–399

    PubMed  Google Scholar 

  • Shriver MD, Mei R, Parra EJ, Sonpar V, Halder I, Tishkoff SA, Schurr TG, Zhadanov SI, Osipova LP, Brutsaert TD, Friedlaender J, Jorde LB, Watkins WS, Bamshad MJ, Gutierrez G, Loi H, Matsuzaki H, Kittles RA, Argyropoulos G, Fernandez JR, Akey JM, Jones KW (2005) Large-scale SNP analysis reveals clustered and continuous patterns of human genetic variation. Hum Genomics 2:81–89

    PubMed  CAS  Google Scholar 

  • Silverman EK, Kwiatkowski DJ, Sylvia JS, Lazarus R, Drazen JM, Lange C, Laird NM, Weiss ST (2003) Family-based association analysis of beta2-adrenergic receptor polymorphisms in the childhood asthma management program. J Allergy Clin Immunol 112:870–876

    Article  PubMed  CAS  Google Scholar 

  • Slatkin M (1991) Inbreeding coefficients and coalescence times. Genet Res 58:167–175

    Article  PubMed  CAS  Google Scholar 

  • Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52:506–516

    PubMed  CAS  Google Scholar 

  • Standardization of Spirometry(1995) 1994 update, American Thoracic Society. Am J Respir Crit Care Med 152:1107–1136

    Google Scholar 

  • Tsai HJ, Choudhry S, Naqvi M, Rodriguez-Cintron W, Burchard EG, Ziv E (2005) Comparison of three methods to estimate genetic ancestry and control for stratification in genetic association studies among admixed populations. Hum Genet (in press)

  • Wacholder S, Rothman N, Caporaso N (2002) Counterpoint: bias from population stratification is not a major threat to the validity of conclusions from epidemiological studies of common polymorphisms and cancer. Cancer Epidemiol Biomarkers Prev 11:513–520

    PubMed  Google Scholar 

  • Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, atopic eczema: ISAAC (1998) The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 351:1225–1232

    Article  Google Scholar 

  • Wright S (1969) Evolution and the genetics of populations. Volume 2: The theory of gene frequencies. University of Chicago Press

  • Zhang S, Zhu X, Zhao H (2003) On a semiparametric test to detect associations between quantitative traits and candidate genes using unrelated individuals. Genet Epidemiol 24:44–56

    Article  PubMed  Google Scholar 

  • Ziv E, Burchard EG (2003) Human population structure and genetic association studies. Pharmacogenomics 4:431–441

    Article  PubMed  Google Scholar 

  • Zondervan KT, Cardon LR, Kennedy SH (2002) What makes a good case-control study? Design issues for complex traits such as endometriosis. Hum Reprod 17:1415–1423

    Article  PubMed  Google Scholar 

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Acknowledgements

The support for this manuscript came from: National Institutes of Health K23 HL04464, HL07185, GM61390, NCMHD Health Disparities Scholar, Extramural Clinical Research Loan Repayment Program for Individuals from Disadvantaged Backgrounds, 2001–2003, American Lung Association of California and The National Center on Minority Health and Health Disparities to EGB, American Lung Association of California Research Training Fellowship to HJT, Sandler Center for Basic Research in Asthma and the Sandler Family Supporting Foundation. We would like to acknowledge the families and the patients for their participation. We would also like to thank the numerous health care providers for their support and participation in the SAGE study. We thank Dr. Mark D. Shriver for his assistance in development of the AIMs and for providing ancestral DNA. We thank Dr. Hua Tang for providing the R code implemented, a global test for estimating recent admixture. We would like to thank Dr. Neil Risch for his support and guidance. Finally, we would like to thank the Sandler Family Foundation, the main sponsor of this project.

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Authors and Affiliations

  1. Department of Medicine, Study of African American, Asthma, Genes and Environments (SAGE), University of California, 0833, San Francisco, CA, 94143-0833, USA

    Hui-Ju Tsai, Jennifer Y. Kho, Nishat Shaikh, Shweta Choudhry, Mariam Naqvi, Daniel Navarro, Henry Matallana, Richard Castro, Shannon Thyne, Elad Ziv & Esteban González Burchard

  2. Lung Biology Center, Study of African American, Asthma, Genes and Environments (SAGE), San Francisco General Hospital, San Francisco, CA, USA

    Hui-Ju Tsai, Jennifer Y. Kho, Nishat Shaikh, Shweta Choudhry, Mariam Naqvi, Daniel Navarro, Henry Matallana, Richard Castro & Esteban González Burchard

  3. Center for Human Genetics, Study of African American, Asthma, Genes and Environments (SAGE), University of California, San Francisco, CA, USA

    Elad Ziv & Esteban González Burchard

  4. Brigham and Women’s Hospital, Boston, MA, USA

    Craig M. Lilly

  5. The James A. Watson Wellness Center, Oakland, CA, USA

    H. George Watson

  6. Children’s Hospital and Research Institute, Oakland, CA, USA

    Kelley Meade

  7. Bay Area Pediatrics, Oakland, CA, USA

    Michael LeNoir

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  1. Hui-Ju Tsai
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  2. Jennifer Y. Kho
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  3. Nishat Shaikh
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  15. Esteban González Burchard
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Correspondence to Hui-Ju Tsai.

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Hui-Ju Tsai and Jennifer Y. Kho have contributed equally to this manuscript

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Tsai, HJ., Kho, J.Y., Shaikh, N. et al. Admixture-matched case-control study: a practical approach for genetic association studies in admixed populations. Hum Genet 118, 626–639 (2006). https://doi.org/10.1007/s00439-005-0080-2

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