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Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations

Nature Genetics volume 43, pages 887–892 (2011)Cite this article

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Abstract

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10−9). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.

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Figure 1: Results of the meta-analysis on the chromosome 1 region of association in African Americans and African Caribbeans.

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Acknowledgements

This work was supported by grants from the Office of the Director, NIH to C.O. and D.L.N. and the National Heart, Lung, and Blood Institute (HL101651 to C.O. and D.L.N.; HL087665 to D.L.N.; HL070831, HL072414 and HL049596 to C.O.; HL064307 and HL064313 to F.D.M.; HL075419, HL65899, HL083069, HL066289, HL087680, HL101543 and HL101651 to S.T.W.; HL079055 to L.K.W.; HL087699, HL49612, HL075417, HL04266 and HL072433 to K.C.B.; HL061768 and HL076647 to F.D.G.; HL087680 to W.J.G.; HL078885 and HL088133 to E.G.B.; HL87665 to D.A.M.; and HL69116, HL69130, HL69149, HL69155, HL69167, HL69170, HL69174 and HL69349 to D.A.M., E.R.B., W.W.B., W.J.C., M.C., K.F.C., S.C.E., E.I. and S.E.W.), the National Institutes of Allergy and Infectious Disease (AI070503 to C.O.; AI079139 and AI061774 to L.K.W.; AI50024, AI44840 and AI41040 to K.C.B.; and AI077439 to E.G.B.), the National Institute of Diabetes and Digestive and Kidney Diseases to L.K.W. (DK064695); the National Institutes of Environmental Health Sciences (ES09606, ES018176 and ES015903 to K.C.B.; ES007048, ES009581, R826708, RD831861 and ES011627 to F.D.G.; ES015794 to E.G.B.; and the Division of Intramural Research, Z01 ES049019, to S.J.L.); the National Center for Research Resources (RR03048 to K.C.B.), the Environmental Protection Agency (83213901 and R-826724 to K.C.B.), the American Asthma Foundation and the Fund for Henry Ford Hospital (to L.K.W.), Mary Beryl Patch Turnbull Scholar Program (to K.C.B.), the National Council of Science and Technology (Mexico) (26206-M to I. Ruczinski), the Centers for Disease Control, US (to I. Ruczinski), the Eudowood Foundation (to N.N.H.); and the Flight Attendant Medical Research Institute (FAMRI), Robert Wood Johnson Foundation (RWJF) Amos Medical Faculty Development Award, the American Asthma Foundation, and the Sandler Foundation (to E.G.B.).

The authors gratefully acknowledge the contributions of H. Moreno-Macias, A. Barraza-Villarreal and M. Ramirez-Aguilar to the MCCAS; R. McConnell, D.C. Thomas, E. Avol, K. Berhane, J. Liu, E. Rappaport and C. Edlund to the CHS; L.N. Borrell, H. Farber, R. Kumar and D. Serebrisky to the GALA and GALA2 studies; S. Thyne to the GALA2 and SAGE studies; M. LeNoir, K. Meade and H. Geoff Watson to the SAGE study; and A.V. Grant, L. Gao, C. Vergara, Y.J. Tsai, P. Gao, M.C. Liu, P. Breysse, M.B. Bracken, J. Hoh, E.W. Pugh, A.F. Scott, G. Abecasis, T. Murray, T. Hand, M. Yang, M. Campbell, C. Foster, J.B. Hetmanski, R. Ashworth, C.M. Ongaco, K.N. Hetrick and K.F. Doheny to the GRAAD study. The authors also acknowledge the support from J. Kiley, S. Banks-Schlegel and W. Gan at the National Heart, Lung, and Blood Institute and all the subjects and families that participated in these studies.

Author information

Author notes

  1. Dara G Torgerson & Dana B Hancock

    Present address: Present addresses: Department of Medicine, University of California San Francisco, San Francisco, California, USA (D.G.T.), Research Triangle Institute International, Research Triangle Park, North Carolina, USA (D.B.H.) and International Agency for Research on Cancer, Lyon, France (I. Romieu).,

  2. Carole Ober and Dan L Nicolae: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Human Genetics, University of Chicago, Chicago, Illinois, USA

    Dara G Torgerson, Daniel Capurso, Rachel A Myers, Rebekah A Abel, Kevin D Ross, Carole Ober & Dan L Nicolae

  2. Center for Genomics, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA

    Elizabeth J Ampleford, Xingnan Li, Eugene R Bleecker & Deborah A Meyers

  3. Westat Inc., Research Triangle Park, North Carolina, USA

    Grace Y Chiu

  4. Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA

    W James Gauderman, James W Baurley, David V Conti, David J Van Den Berg, Muhammad T Salam, Hita Vora, Xia Li & Frank D Gilliland

  5. Department of Medicine, University of California San Francisco, San Francisco, California, USA

    Christopher R Gignoux, Celeste Eng, Lindsey A Roth, Donglei Hu, Joshua Galanter, Scott Huntsman & Esteban G Burchard

  6. Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, Arizona, USA

    Penelope E Graves, Debra A Stern & Fernando D Martinez

  7. Department of Medicine, Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Blanca E Himes, Elliott Israel, Benjamin A Raby & Scott T Weiss

  8. Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan, USA

    Albert M Levin

  9. Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA

    Rasika A Mathias, Nicholas Rafaels, Alkis Togias, Nadia N Hansel, Gregory B Diette, N Franklin Adkinson, Vito J Mantese & Kathleen C Barnes

  10. Department of Health and Human Services, Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA

    Dana B Hancock, Min Shi & Stephanie J London

  11. Division of Pediatric Pulmonology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Juan C Celedón

  12. Hospital Nacional de Niños, San José, Costa Rica

    Manuel Soto-Quiros & Lydiana Avila

  13. Instituto Nacional de Salud Publica, Mexico City, Mexico

    Isabelle Romieu

  14. Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA

    Nadia N Hansel, Gregory B Diette, Jean G Ford & Terri H Beaty

  15. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA

    Ryan D Hernandez & Esteban G Burchard

  16. Department of Medicine, Northwestern University, Chicago, Illinois, USA

    Pedro C Avila

  17. Centro de Neumologia Pediatrica, San Juan, Puerto Rico

    Jose R Rodriquez-Santana

  18. Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico

    Rocio Chapela

  19. Veterans Affairs Medical Center, San Juan, Puerto Rico

    William Rodriguez-Cintron

  20. Department of Community and Family Medicine, Howard University College of Medicine, Washington, DC, USA

    Mezbah U Faruque

  21. Department of Microbiology, Howard University, Washington, DC, USA

    Georgia M Dunston

  22. Faculty of Medical Sciences, University of the West Indies, Cave Hill Campus and Queen Elizabeth Hospital, St. Michael, Barbados

    Harold R Watson

  23. The Lerner Research Institute and Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA

    Serpil C Ezurum

  24. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA

    Liming Liang

  25. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA

    Liming Liang

  26. Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland, USA

    Ingo Ruczinski

  27. Respiratory Medicine, Imperial College School of Medicine, London, UK

    Kian Fan Chung

  28. Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA

    William J Calhoun

  29. Department of Medicine, Washington University, St. Louis, Missouri, USA

    Mario Castro

  30. Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico

    Juan J Sienra-Monge & Blanca del Rio-Navarro

  31. Department of Pediatrics, University of Freiburg, Freiburg, Germany

    Klaus A Deichmann & Andrea Heinzmann

  32. Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Sally E Wenzel

  33. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

    William W Busse

  34. Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

    James E Gern & Robert F Lemanske Jr

  35. Department of Internal Medicine, Center for Health Services Research, Henry Ford Health System, Detroit, Michigan, USA

    L Keoki Williams

  36. Department of Medicine, University of Chicago, Chicago, Illinois, USA

    Dan L Nicolae

  37. Department of Statistics, University of Chicago, Chicago, Illinois, USA

    Dan L Nicolae

Authors
  1. Carole Ober
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  2. Dan L Nicolae
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Consortia

Mexico City Childhood Asthma Study (MCAAS)

  • Dara G Torgerson
  • , Elizabeth J Ampleford
  • , Grace Y Chiu
  • , W James Gauderman
  • , Christopher R Gignoux
  • , Penelope E Graves
  • , Blanca E Himes
  • , Albert M Levin
  • , Rasika A Mathias
  • , Dana B Hancock
  • , James W Baurley
  • , Celeste Eng
  • , Debra A Stern
  • , Juan C Celedón
  • , Nicholas Rafaels
  • , Daniel Capurso
  • , David V Conti
  • , Lindsey A Roth
  • , Manuel Soto-Quiros
  • , Alkis Togias
  • , Xingnan Li
  • , Rachel A Myers
  • , Isabelle Romieu
  • , David J Van Den Berg
  • , Donglei Hu
  • , Nadia N Hansel
  • , Ryan D Hernandez
  • , Elliott Israel
  • , Muhammad T Salam
  • , Joshua Galanter
  • , Pedro C Avila
  • , Lydiana Avila
  • , Jose R Rodriquez-Santana
  • , Rocio Chapela
  • , William Rodriguez-Cintron
  • , Gregory B Diette
  • , N Franklin Adkinson
  • , Rebekah A Abel
  • , Kevin D Ross
  • , Min Shi
  • , Mezbah U Faruque
  • , Georgia M Dunston
  • , Harold R Watson
  • , Vito J Mantese
  • , Serpil C Ezurum
  • , Liming Liang
  • , Ingo Ruczinski
  • , Jean G Ford
  • , Scott Huntsman
  • , Kian Fan Chung
  • , Hita Vora
  • , Xia Li
  • , William J Calhoun
  • , Mario Castro
  • , Juan J Sienra-Monge
  • , Blanca del Rio-Navarro
  • , Klaus A Deichmann
  • , Andrea Heinzmann
  • , Sally E Wenzel
  • , William W Busse
  • , James E Gern
  • , Robert F Lemanske Jr
  • , Terri H Beaty
  • , Eugene R Bleecker
  • , Benjamin A Raby
  • , Deborah A Meyers
  •  & Stephanie J London

Children's Health Study (CHS) and HARBORS study

  • Frank D Gilliland

Genetics of Asthma in Latino Americans (GALA) Study, the Study of Genes-Environment and Admixture in Latino Americans (GALA2) and the Study of African Americans, Asthma, Genes & Environments (SAGE)

  • Esteban G Burchard

Childhood Asthma Research and Education (CARE) Network

  • Fernando D Martinez

Childhood Asthma Management Program (CAMP)

  • Scott T Weiss

Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE)

  • L Keoki Williams

Genetic Research on Asthma in the African Diaspora (GRAAD) Study

  • Kathleen C Barnes

Contributions

E.R.B., B.A.R., D.A.M., S.J.L., F.D.G., W.J.G., E.G.B., F.D.M., S.T.W., L.K.W., K.C.B., C.O. and D.L.N. conceived and designed the experiments. W.J.G., A.M.L., C.E., D.J.V.D.B., M.T.S., K.D.R., E.R.B., D.A.M., S.T.W., E.G.B. and L.K.W. performed the experiments. D.G.T., E.J.A., G.Y.C., W.J.G., C.R.G., B.E.H., A.M.L., R.A. Mathias, D.B.H., J.W.B., D.A.S., N.R., D.C., D.V.C., L.A.R., Xingnan L., D.H., R.D.H., J.G., M.S., V.J.M., L.L., I. Ruczinski, S.H., H.V., Xia L., T.H.B., E.R.B., D.A.M. and D.L.N. performed statistical analysis. D.G.T., E.J.A., G.Y.C., W.J.G., C.R.G., B.E.H., A.M.L., R.A. Mathias, D.B.H., J.W.B., C.E., D.A.S., N.R., D.C., D.V.C., L.A.R., Xingnan L., R.A. Myers, D.H., M.T.S., J.G., V.J.M., L.L., I. Romieu, S.H., H.V., Xia L., T.H.B., E.R.B., D.A.M., F.D.G., L.K.W., K.C.B. and D.L.N. analyzed the data. P.E.G., A.M.L., J.C.C., D.V.C., M.S.-Q., A.T., I. Romieu, N.N.H., E.I., M.T.S., J.G., P.C.A., L.A., J.R.R.-S., R.C., W.R.-C., G.B.D., N.F.A., M.S., M.U.F., G.M.D., H.R.W., S.C.E., J.G.F., K.F.C., W.J.C., M.C., J.-J.S.-M., B.d.R.-N., K.A.D., A.H., S.E.W., W.W.B., J.E.G., R.F.L., E.R.B., D.A.M., S.J.L., F.D.G., F.D.M., S.T.W., L.K.W., E.G.B., K.C.B. and C.O. contributed reagents, materials and analysis tools. D.G.T., G.Y.C., W.J.G., B.E.H., A.M.L., R.A. Mathias, D.B.H., E.R.B., B.A.R., D.A.M., S.J.L., F.D.G., E.G.B., F.D.M., S.T.W., L.K.W., K.C.B., C.O. and D.L.N. wrote the paper. R.A.A. coordinated the study.

Corresponding author

Correspondence to Dan L Nicolae.

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Mexico City Childhood Asthma Study (MCAAS)., Children's Health Study (CHS) and HARBORS study., Genetics of Asthma in Latino Americans (GALA) Study, the Study of Genes-Environment and Admixture in Latino Americans (GALA2) and the Study of African Americans, Asthma, Genes & Environments (SAGE). et al. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat Genet 43, 887–892 (2011). https://doi.org/10.1038/ng.888

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