Genome Wide Association Studies (GWAS) and Their Clinical Applications in Asthma

  • Xiaojing Liu
  • Yi Jia
Part of the Translational Bioinformatics book series (TRBIO, volume 12)


Asthma is a chronic lower respiratory tract disease with strong heterogeneity, both environmental and genetic factors contribute to its development, progress and exacerbation. More than 10 years ago, Genome-Wide Association Study (GWAS) was developed and used broadly to study the genes related to asthma susceptibilities and responsiveness to asthma medications. In this chapter, the development and evolution of GWAS from previous approaches for new genetic biomarker discovery will be introduced, followed by its applications in asthma. Furthermore, the major limitations of GWAS and the potential solutions will also be discussed. Although GWAS has been successfully applied in finding the asthma-associated loci, however, more potential applications in the fields of understanding the asthma pathogenesis and guiding the treatments still need to be considered.


Genome Wide Association Study (GWAS) Asthma Single nucleotide polymorphisms (SNPs) Gene 


  1. 1.
    Bonnelykke K, Ober C. Leveraging gene-environment interactions and endotypes for asthma gene discovery. J Allergy Clin Immunol. 2016;137(3):667–79. [PubMed: 26947980]CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Martinez FD, Vercelli D. Asthma. Lancet. 2013;382(9901):1360–72. [PubMed: 24041942]CrossRefPubMedGoogle Scholar
  3. 3.
    Ober C, Yao TC. The genetics of asthma and allergic disease: a twenty-first century perspective. Immunol Rev. 2011;242(1):10–30. [PubMed: 21682736]CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Manolio TA, Collins FS. The HapMap and genome-wide association studies in diagnosis and therapy. Annu Rev Med. 2009;60:443–56. [PubMed: 19630580]CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Howie BN, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 2009;5(6):e1000529. [PubMed: 19543373]CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ober C. Asthma genetics in the post-GWAS era. Ann Am Thorac Soc. 2016;13(Suppl 1):S85–90. [PubMed: 27027959]PubMedPubMedCentralGoogle Scholar
  7. 7.
    Grant SF, Hakonarson H. Microarray technology and applications in the arena of genome-wide association. Clin Chem. 2008;54(7):1116–24. [PubMed: 18499899]CrossRefPubMedGoogle Scholar
  8. 8.
    Mathias RA. Introduction to genetics and genomics in asthma: genetics of asthma. Adv Exp Med Biol. 2014;795:125–55. [PubMed: 24162907]CrossRefPubMedGoogle Scholar
  9. 9.
    Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308(5720):385–9. [PubMed: 15761122]CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Dewan A, Liu M, Hartman S, Zhang SS, Liu DT, Zhao C, et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science. 2006;314(5801):989–92. [PubMed: 17053108]CrossRefPubMedGoogle Scholar
  11. 11.
    Wellcome Trust Case Control C. Genome-wide association study of 14,000 cases of seven common diseases and 3000 shared controls. Nature. 2007;447(7145):661–78. [PubMed: 17554300]CrossRefGoogle Scholar
  12. 12.
    Metzker ML. Sequencing technologies – the next generation. Nat Rev Genet. 2010;11(1):31–46. [PubMed: 19997069]CrossRefPubMedGoogle Scholar
  13. 13.
    Teer JK, Mullikin JC. Exome sequencing: the sweet spot before whole genomes. Hum Mol Genet. 2010;19(R2):R145–51. [PubMed: 20705737]CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Luo L, Boerwinkle E, Xiong M. Association studies for next-generation sequencing. Genome Res. 2011;21(7):1099–108. [PubMed: 21521787]CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Visscher PM, Wray NR, Zhang Q, Sklar P, McCarthy MI, Brown MA, et al. 10 years of GWAS discovery: biology, function, and translation. Am J Hum Genet. 2017;101(1):5–22. [PubMed: 28686856]CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Torgerson DG, Ampleford EJ, Chiu GY, Gauderman WJ, Gignoux CR, Graves PE, et al. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat Genet. 2011;43(9):887–92. [PubMed: 21804549]CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Mathias RA, Grant AV, Rafaels N, Hand T, Gao L, Vergara C, et al. A genome-wide association study on African-ancestry populations for asthma. J Allergy Clin Immunol. 2010;125(2):336–346 e334. [PubMed: 19910028]CrossRefPubMedGoogle Scholar
  18. 18.
    Garcia-Sanchez A, Isidoro-Garcia M, Garcia-Solaesa V, Sanz C, Hernandez-Hernandez L, Padron-Morales J, et al. Genome-wide association studies (GWAS) and their importance in asthma. Allergol Immunopathol. 2015;43(6):601–8. [PubMed: 25433770]CrossRefGoogle Scholar
  19. 19.
    Loser S, Gregory LG, Zhang Y, Schaefer K, Walker SA, Buckley J, et al. Pulmonary ORMDL3 is critical for induction of Alternaria-induced allergic airways disease. J Allergy Clin Immunol. 2017;139(5):1496–1507 e1493. [PubMed: 27623174]CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Yan Q, Brehm J, Pino-Yanes M, Forno E, Lin J, Oh SS, et al. A meta-analysis of genome-wide association studies of asthma in Puerto Ricans. Eur Respir J. 2017;49(5). [PubMed: 28461288]CrossRefPubMedGoogle Scholar
  21. 21.
    Das S, Miller M, Broide DH. Chromosome 17q21 genes ORMDL3 and GSDMB in asthma and immune diseases. Adv Immunol. 2017;135:1–52. [PubMed: 28826527]CrossRefPubMedGoogle Scholar
  22. 22.
    Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010;363(13):1211–21. [PubMed: 20860503]CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Sharma S, Chhabra D, Kho AT, Hayden LP, Tantisira KG, Weiss ST. The genomic origins of asthma. Thorax. 2014;69(5):481–7. [PubMed: 24668408]CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ferreira MA, Matheson MC, Duffy DL, Marks GB, Hui J, Le Souef P, et al. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet. 2011;378(9795):1006–14. [PubMed: 21907864]CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG, Martinez FD. A polymorphism* in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol. 1999;20(5):976–83. [PubMed: 10226067]CrossRefPubMedGoogle Scholar
  26. 26.
    Li X, Howard TD, Zheng SL, Haselkorn T, Peters SP, Meyers DA, et al. Genome-wide association study of asthma identifies RAD50-IL13 and HLA-DR/DQ regions. J Allergy Clin Immunol. 2010;125(2):328–335 e311. [PubMed: 20159242]CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Almoguera B, Vazquez L, Mentch F, Connolly J, Pacheco JA, Sundaresan AS, et al. Identification of four novel loci in asthma in European American and African American populations. Am J Respir Crit Care Med. 2017;195(4):456–63. [PubMed: 27611488]CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    White MJ, Risse-Adams O, Goddard P, Contreras MG, Adams J, Hu D, et al. Novel genetic risk factors for asthma in African American children: precision Medicine and the SAGE II study. Immunogenetics. 2016;68(6–7):400–391. [PubMed: 27142222]Google Scholar
  29. 29.
    Hirota T, Takahashi A, Kubo M, Tsunoda T, Tomita K, Doi S, et al. Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population. Nat Genet. 2011;43(9):893–6. [PubMed: 21804548]CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Rava M, Smit LA, Nadif R. Gene-environment interactions in the study of asthma in the postgenomewide association studies era. Curr Opin Allergy Clin Immunol. 2015;15(1):70–8. [PubMed: 25479314]CrossRefPubMedGoogle Scholar
  31. 31.
    Du R, Litonjua AA, Tantisira KG, Lasky-Su J, Sunyaev SR, Klanderman BJ, et al.: Genome-wide association study reveals class I MHC-restricted T cell-associated molecule gene (CRTAM) variants interact with vitamin D levels to affect asthma exacerbations. J Allergy Clin Immunol 2012, 129(2):368–373. 373 e361–365. [PubMed: 22051697].CrossRefGoogle Scholar
  32. 32.
    Meyers DA, Bleecker ER, Holloway JW, Holgate ST. Asthma genetics and personalised medicine. Lancet Respir Med. 2014;2(5):405–15. [PubMed: 24794577]CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Bonnelykke K, Sleiman P, Nielsen K, Kreiner-Moller E, Mercader JM, Belgrave D, et al. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat Genet. 2014;46(1):51–5. [PubMed: 24241537]CrossRefPubMedGoogle Scholar
  34. 34.
    McGeachie MJ, Wu AC, Tse SM, Clemmer GL, Sordillo J, Himes BE, et al. CTNNA3 and SEMA3D: Promising loci for asthma exacerbation identified through multiple genome-wide association studies. J Allergy Clin Immunol. 2015;136(6):1503–10. [PubMed: 26073756]CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Park HW, Tantisira KG. Genetic signatures of asthma exacerbation. Allergy, Asthma Immunol Res. 2017;9(3):191–9. [PubMed: 28293925]CrossRefGoogle Scholar
  36. 36.
    Xu M, Tantisira KG, Wu A, Litonjua AA, Chu JH, Himes BE, et al. Genome wide association study to predict severe asthma exacerbations in children using random forests classifiers. BMC Med Genet. 2011;12:90. [PubMed: 21718536]CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Nieuwenhuis MA, Vonk JM, Himes BE, Sarnowski C, Minelli C, Jarvis D, et al. PTTG1IP and MAML3, novel genomewide association study genes for severity of hyperresponsiveness in adult asthma. Allergy. 2017;72(5):792–801. [PubMed: 27709636]CrossRefPubMedGoogle Scholar
  38. 38.
    Tantisira KG, Lasky-Su J, Harada M, Murphy A, Litonjua AA, Himes BE, et al. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N Engl J Med. 2011;365(13):1173–83. [PubMed: 21991891]CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Dahlin A, Litonjua A, Irvin CG, Peters SP, Lima JJ, Kubo M, et al. Genome-wide association study of leukotriene modifier response in asthma. Pharmacogenomics J. 2016;16(2):151–7. [PubMed: 26031901]CrossRefPubMedGoogle Scholar
  40. 40.
    Sleiman PM, Flory J, Imielinski M, Bradfield JP, Annaiah K, Willis-Owen SA, et al. Variants of DENND1B associated with asthma in children. N Engl J Med. 2010;362(1):36–44. [PubMed: 20032318]CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Xiaojing Liu
    • 1
  • Yi Jia
    • 2
  1. 1.Geriatric Department of Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghaiChina
  2. 2.SomaLogic Inc.BoulderUSA

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