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Population stratification confounds genetic association studies among Latinos

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Abstract

In the United States, asthma prevalence and mortality are the highest among Puerto Ricans and the lowest among Mexicans. Case-control association studies are a powerful strategy for identifying genes of modest effect in complex diseases. However, studies of complex disorders in admixed populations such as Latinos may be confounded by population stratification. We used ancestry informative markers (AIMs) to identify and correct for population stratification among Mexican and Puerto Rican subjects participating in case-control studies of asthma. Three hundred and sixty-two subjects with asthma (Mexican: 181, Puerto Rican: 181) and 359 ethnically matched controls (Mexican: 181, Puerto Rican: 178) were genotyped for 44 AIMs. We observed a greater than expected degree of association between pairs of AIMs on different chromosomes in Mexicans (P<0.00001) and Puerto Ricans (P<0.00002) providing evidence for population substructure and/or recent admixture. To assess the effect of population stratification on association studies of asthma, we measured differences in genetic background of cases and controls by comparing allele frequencies of the 44 AIMs. Among Puerto Ricans but not in Mexicans, we observed a significant overall difference in allele frequencies between cases and controls (P=0.0002); of 44 AIMs tested, 8 (18%) were significantly associated with asthma. However, after adjustment for individual ancestry, only two of these markers remained significantly associated with the disease. Our findings suggest that empirical assessment of the effects of stratification is critical to appropriately interpret the results of case-control studies in admixed populations.

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Acknowledgements

The authors would like to acknowledge the families and the patients for their participation. The authors would also like to thank the numerous health care providers and community clinics for their support and participation in the GALA Study. In addition to the primary clinical centers of the investigators, participating community clinics and hospitals include: La Clinica de La Raza, Oakland, CA; UCSF-Children’s Hospital of Oakland Pediatric Clinical Research Center, Oakland, CA; General Clinical Research Center, SFGH, San Francisco, CA; Alliance Medical Center, Healdsburg, CA; Santa Clara Valley Medical Center, San José, CA; Fair Oaks Family Health Center, Redwood City, CA; Clinica de Salud del Valle de Salinas, Salinas, CA; Natividad Medical Center, Salinas, CA; Asthma Education and Management Program, Community Medical Centers, Fresno, CA., Diagnostic Health Centers of: Corozal, Naranjito, Catano, Orocovis, Barranquitas, and San Antonio Hospital of Mayaguez. The authors would also like to acknowledge Monica Toscano, MariaElena Alioto, Carmen Jimenez, Yannett Marcano, Pedro Yapor, MD, Alma Ortiz, MD, Lisandra Perez, MD, and Sheila Gonzalez MD for their assistance with recruitment. The authors would like to especially thank the Jeffrey M. Drazen, MD, Scott Weiss, MD, Ed Silverman, MD, PhD, Homer A. Boushey, MD and Jean G. Ford, MD for all of their effort towards the creation of the GALA Study. Finally, the authors would like to thank the Sandler Family Supporting Foundation, the primary sponsor of this investigation. 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, the Resource Centers for Minority Aging Research (RCMAR P30-AG15272) from the National Institute on Aging, the National Institute of Nursing Research, American Lung Association of California and The National Center on Minority Health and Health Disparities to EGB], (HL51823 and 3M01RR000083-38S30488 to the Asthma Clinical Research Network), SFGH General Clinical Research Center M01RR00083-41, U01-HL 65899, UCSF-Children’s Hospital of Oakland Pediatric Clinical Research Center (M01 RR01271), Oakland, CA, K12 AR47659, CRTG-02-084-01-CCE, Sandler Center for Basic Research in Asthma and the Sandler Family Supporting Foundation.

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Authors and Affiliations

  1. University of California, San Francisco, CA, 94143-0833, USA

    Shweta Choudhry, Natasha E. Coyle, Keyan Salari, Denise Lind, Suzanne L. Clark, Hui-Ju Tsai, Mariam Naqvi, Angie Phong, Ngim Ung, Henry Matallana, Pedro C. Avila, Richard Castro, Natalie C. Battle, Eliseo J. Perez-Stable, Pui-Yan Kwok, Dean Sheppard, Elad Ziv & Esteban Gonzàlez Burchard

  2. Lung Biology Center, San Francisco General Hospital, San Francisco, CA, USA

    Shweta Choudhry, Natasha E. Coyle, Keyan Salari, Suzanne L. Clark, Hui-Ju Tsai, Mariam Naqvi, Ngim Ung, Henry Matallana, Richard Castro, Natalie C. Battle, Dean Sheppard & Esteban Gonzàlez Burchard

  3. Fred Hutchinson Cancer Research Cancer Center, Seattle, WA, USA

    Hua Tang

  4. San Juan VAMC, University of Puerto Rico School of Medicine, San Juan, PR, USA

    Jesus Casal, Alfonso Torres, Sylvette Nazario & William Rodriguez-Cintron

  5. Department of Anthropology, The Pennsylvania State University, University Park, PA, USA

    Mark D. Shriver

  6. Center for Human Genetics, University of California, San Francisco, CA, USA

    Neil Risch

  7. Division of Research, Kaiser Permanente, Oakland, CA, USA

    Neil Risch

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  1. Shweta Choudhry
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  2. Natasha E. Coyle
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  3. Hua Tang
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  4. Keyan Salari
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  5. Denise Lind
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  8. Mariam Naqvi
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  9. Angie Phong
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  10. Ngim Ung
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  15. Sylvette Nazario
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  16. Richard Castro
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  17. Natalie C. Battle
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  18. Eliseo J. Perez-Stable
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  21. Mark D. Shriver
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  25. Esteban Gonzàlez Burchard
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Genetics of Asthma in Latino Americans (GALA) Study

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Correspondence to Esteban Gonzàlez Burchard.

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Shweta Choudhry, Natasha E. Coyle are authors contributed equally to this manuscript.

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Choudhry, S., Coyle, N.E., Tang, H. et al. Population stratification confounds genetic association studies among Latinos. Hum Genet 118, 652–664 (2006). https://doi.org/10.1007/s00439-005-0071-3

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