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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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

    • Dara G Torgerson
    •  & Dana B Hancock

    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).

    • Carole Ober
    •  & Dan L Nicolae

    These authors contributed equally to this work.

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. Channing Laboratory, Department of Medicine, 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. Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, 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. Center for Health Services Research, Department of Internal Medicine, 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

Consortia

  1. Mexico City Childhood Asthma Study (MCAAS)

  2. Children's Health Study (CHS) and HARBORS study

  3. 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)

  4. Childhood Asthma Research and Education (CARE) Network

  5. Childhood Asthma Management Program (CAMP)

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

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

Authors

  1. Search for Carole Ober in:

  2. Search for Dan L Nicolae in:

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dan L Nicolae.

Supplementary information

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DOI

https://doi.org/10.1038/ng.888

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