Allergy Asthma Immunol Res.  2019 Mar;11(2):170-187. 10.4168/aair.2019.11.2.170.

Lessons Learned From GWAS of Asthma

• Kim KW
• Ober C

• KMID: 2431850
• DOI: http://doi.org/10.4168/aair.2019.11.2.170

Abstract

Asthma is a common complex disease of the airways. Genome-wide association studies (GWASs) of asthma have identified many risk alleles and loci that have been replicated in worldwide populations. Although the risk alleles identified by GWAS have small effects and explain only a small portion of prevalence, the discovery of asthma loci can provide an understanding of its genetic architecture and the molecular pathways involved in disease pathogenesis. These discoveries can translate into advances in clinical care by identifying therapeutic targets, preventive strategies and ultimately approaches for personalized medicine. In this review, we summarize results from GWAS of asthma from the past 10 years and the insights gleaned from these discoveries.

Keyword

Asthma; genome-wide association study

MeSH Terms

Alleles
Asthma*
Genome-Wide Association Study
Precision Medicine
Prevalence

Figure

• 

  Figure Word cloud consisting of asthma risk genes from asthma GWASs (see Table 2 for references). Genes at genome-wide significant loci were selected based on the nearest gene. Word weight was assigned based on the number of times these genes were at loci that met the criteria for genome-wide significance. Word cloud was made using R package ‘wordcloud’ version 2.5. Figure drawn by H. Jang. GWAS, genome-wide association study.

Reference

1. Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008; 372:1107–1119.

2. Los H, Koppelman GH, Postma DS. The importance of genetic influences in asthma. Eur Respir J. 1999; 14:1210–1227.

3. Vercelli D. Discovering susceptibility genes for asthma and allergy. Nat Rev Immunol. 2008; 8:169–182.

4. Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nat Rev Genet. 2005; 6:95–108.

5. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature. 2007; 448:470–473.

6. Ober C, Vercelli D. Gene-environment interactions in human disease: nuisance or opportunity? Trends Genet. 2011; 27:107–115.

7. Ober C. Asthma genetics in the post-GWAS era. Ann Am Thorac Soc. 2016; 13:Suppl 1. S85–S90.

8. Bønnelykke K, Ober C. Leveraging gene-environment interactions and endotypes for asthma gene discovery. J Allergy Clin Immunol. 2016; 137:667–679.

9. Bernstein DI. Genetics of occupational asthma. Curr Opin Allergy Clin Immunol. 2011; 11:86–89.

10. Park SM, Park JS, Park HS, Park CS. Unraveling the genetic basis of aspirin hypersensitivity in asthma beyond arachidonate pathways. Allergy Asthma Immunol Res. 2013; 5:258–276.

11. Dahlin A, Weiss ST. Genetic and epigenetic components of aspirin-exacerbated respiratory disease. Immunol Allergy Clin North Am. 2016; 36:765–789.

12. Davis JS, Weiss ST, Tantisira KG. Asthma pharmacogenomics: 2015 update. Curr Allergy Asthma Rep. 2015; 15:42.

13. Park HW, Tantisira KG. Genetic signatures of asthma exacerbation. Allergy Asthma Immunol Res. 2017; 9:191–199.

14. Demenais F, Margaritte-Jeannin P, Barnes KC, Cookson WO, Altmüller J, Ang W, et al. Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. Nat Genet. 2018; 50:42–53.

15. Stein MM, Thompson EE, Schoettler N, Helling BA, Magnaye KM, Stanhope C, et al. A decade of research on the 17q12-21 asthma locus: piecing together the puzzle. J Allergy Clin Immunol. 2018; 142:749–764.e3.

16. 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; 363:1211–1221.

17. Bouzigon E, Corda E, Aschard H, Dizier MH, Boland A, Bousquet J, et al. Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med. 2008; 359:1985–1994.

18. Çalışkan M, Bochkov YA, Kreiner-Møller E, Bønnelykke K, Stein MM, Du G, et al. Rhinovirus wheezing illness and genetic risk of childhood-onset asthma. N Engl J Med. 2013; 368:1398–1407.

19. 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; 43:887–892.

20. Das S, Miller M, Broide DH. Chromosome 17q21 genes ORMDL3 and GSDMB in asthma and immune diseases. Adv Immunol. 2017; 135:1–52.

21. Pickrell JK, Berisa T, Liu JZ, Ségurel L, Tung JY, Hinds DA. Detection and interpretation of shared genetic influences on 42 human traits. Nat Genet. 2016; 48:709–717.

22. Bønnelykke K, Sleiman P, Nielsen K, Kreiner-Møller 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; 46:51–55.

23. Bochkov YA, Watters K, Ashraf S, Griggs TF, Devries MK, Jackson DJ, et al. Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication. Proc Natl Acad Sci U S A. 2015; 112:5485–5490.

24. Bønnelykke K, Coleman AT, Evans MD, Thorsen J, Waage J, Vissing NH, et al. Cadherin-related family member 3 genetics and rhinovirus C respiratory illnesses. Am J Respir Crit Care Med. 2018; 197:589–594.

25. 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; 136:1503–1510.

26. Ferreira MA, Matheson MC, Tang CS, Granell R, Ang W, Hui J, et al. Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype. J Allergy Clin Immunol. 2014; 133:1564–1571.

27. Yatagai Y, Sakamoto T, Yamada H, Masuko H, Kaneko Y, Iijima H, et al. Genomewide association study identifies HAS2 as a novel susceptibility gene for adult asthma in a Japanese population. Clin Exp Allergy. 2014; 44:1327–1334.

28. Siroux V, González JR, Bouzigon E, Curjuric I, Boudier A, Imboden M, et al. Genetic heterogeneity of asthma phenotypes identified by a clustering approach. Eur Respir J. 2014; 43:439–452.

29. Forno E, Lasky-Su J, Himes B, Howrylak J, Ramsey C, Brehm J, et al. Genome-wide association study of the age of onset of childhood asthma. J Allergy Clin Immunol. 2012; 130:83–90.e4.

30. Myers RA, Scott NM, Gauderman WJ, Qiu W, Mathias RA, Romieu I, et al. Genome-wide interaction studies reveal sex-specific asthma risk alleles. Hum Mol Genet. 2014; 23:5251–5259.

31. Ege MJ, Strachan DP, Cookson WO, Moffatt MF, Gut I, Lathrop M, et al. Gene-environment interaction for childhood asthma and exposure to farming in Central Europe. J Allergy Clin Immunol. 2011; 127:138–144. 144.e1–134.

32. Newton KM, Peissig PL, Kho AN, Bielinski SJ, Berg RL, Choudhary V, et al. Validation of electronic medical record-based phenotyping algorithms: results and lessons learned from the eMERGE network. J Am Med Inform Assoc. 2013; 20:e147–54.

33. Gottesman O, Kuivaniemi H, Tromp G, Faucett WA, Li R, Manolio TA, et al. The Electronic Medical Records and Genomics (eMERGE) Network: past, present, and future. Genet Med. 2013; 15:761–771.

34. 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; 195:456–463.

35. Drake KA, Torgerson DG, Gignoux CR, Galanter JM, Roth LA, Huntsman S, et al. A genome-wide association study of bronchodilator response in Latinos implicates rare variants. J Allergy Clin Immunol. 2014; 133:370–378.

36. Israel E, Lasky-Su J, Markezich A, Damask A, Szefler SJ, Schuemann B, et al. Genome-wide association study of short-acting β₂-agonists. A novel genome-wide significant locus on chromosome 2 near ASB3 . Am J Respir Crit Care Med. 2015; 191:530–537.

37. Himes BE, Qiu W, Klanderman B, Ziniti J, Senter-Sylvia J, Szefler SJ, et al. ITGB5 and AGFG1 variants are associated with severity of airway responsiveness. BMC Med Genet. 2013; 14:86.

38. 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; 72:792–801.

39. Himes BE, Hunninghake GM, Baurley JW, Rafaels NM, Sleiman P, Strachan DP, et al. Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene. Am J Hum Genet. 2009; 84:581–593.

40. Gudbjartsson DF, Bjornsdottir US, Halapi E, Helgadottir A, Sulem P, Jonsdottir GM, et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet. 2009; 41:342–347.

41. Jacobsen HP, Herskind AM, Nielsen BW, Husby S. IgE in unselected like-sexed monozygotic and dizygotic twins at birth and at 6 to 9 years of age: high but dissimilar genetic influence on IgE levels. J Allergy Clin Immunol. 2001; 107:659–663.

42. Strachan DP, Wong HJ, Spector TD. Concordance and interrelationship of atopic diseases and markers of allergic sensitization among adult female twins. J Allergy Clin Immunol. 2001; 108:901–907.

43. Weidinger S, Gieger C, Rodriguez E, Baurecht H, Mempel M, Klopp N, et al. Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus. PLoS Genet. 2008; 4:e1000166.

44. Granada M, Wilk JB, Tuzova M, Strachan DP, Weidinger S, Albrecht E, et al. A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study. J Allergy Clin Immunol. 2012; 129:840–845.e21.

45. Pino-Yanes M, Gignoux CR, Galanter JM, Levin AM, Campbell CD, Eng C, et al. Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos. J Allergy Clin Immunol. 2015; 135:1502–1510.

46. Yatagai Y, Sakamoto T, Masuko H, Kaneko Y, Yamada H, Iijima H, et al. Genome-wide association study for levels of total serum IgE identifies HLA-C in a Japanese population. PLoS One. 2013; 8:e80941.

47. Levin AM, Mathias RA, Huang L, Roth LA, Daley D, Myers RA, et al. A meta-analysis of genome-wide association studies for serum total IgE in diverse study populations. J Allergy Clin Immunol. 2013; 131:1176–1184.

48. Bønnelykke K, Matheson MC, Pers TH, Granell R, Strachan DP, Alves AC, et al. Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization. Nat Genet. 2013; 45:902–906.

49. Ferreira MA, Vonk JM, Baurecht H, Marenholz I, Tian C, Hoffman JD, et al. Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology. Nat Genet. 2017; 49:1752–1757.

50. GTEx Consortium. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015; 348:648–660.

51. Nicolae DL, Gamazon E, Zhang W, Duan S, Dolan ME, Cox NJ. Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet. 2010; 6:e1000888.

52. Li X, Hastie AT, Hawkins GA, Moore WC, Ampleford EJ, Milosevic J, et al. eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS-identified asthma genes. Allergy. 2015; 70:1309–1318.

53. Ferreira MA, Jansen R, Willemsen G, Penninx B, Bain LM, Vicente CT, et al. Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling. J Allergy Clin Immunol. 2017; 139:1148–1157.

54. Ferreira MA, Vonk JM, Baurecht H, Marenholz I, Tian C, Hoffman JD, et al. Eleven loci with new reproducible genetic associations with allergic disease risk. J Allergy Clin Immunol. 2018.

55. Luo W, Obeidat M, Di Narzo AF, Chen R, Sin DD, Paré PD, et al. Airway epithelial expression quantitative trait loci reveal genes underlying asthma and other airway diseases. Am J Respir Cell Mol Biol. 2016; 54:177–187.

56. GTEx Consortium. Genetic effects on gene expression across human tissues. Nature. 2017; 550:204–213.

57. Kim SH, Cho BY, Park CS, Shin ES, Cho EY, Yang EM, et al. Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis. Clin Exp Allergy. 2009; 39:203–212.

58. Kim JH, Park BL, Cheong HS, Bae JS, Park JS, Jang AS, et al. Genome-wide and follow-up studies identify CEP68 gene variants associated with risk of aspirin-intolerant asthma. PLoS One. 2010; 5:e13818.

59. Shin SW, Park J, Kim YJ, Uh ST, Choi BW, Kim MK, et al. A highly sensitive and specific genetic marker to diagnose aspirin-exacerbated respiratory disease using a genome-wide association study. DNA Cell Biol. 2012; 31:1604–1609.

60. Park BL, Kim TH, Kim JH, Bae JS, Pasaje CF, Cheong HS, et al. Genome-wide association study of aspirin-exacerbated respiratory disease in a Korean population. Hum Genet. 2013; 132:313–321.

61. Kim SH, Cho BY, Choi H, Shin ES, Ye YM, Lee JE, et al. The SNP rs3128965 of HLA-DPB1 as a genetic marker of the AERD phenotype. PLoS One. 2014; 9:e111220.

62. Kim JH, Cheong HS, Park JS, Jang AS, Uh ST, Kim YH, et al. A genome-wide association study of total serum and mite-specific IgEs in asthma patients. PLoS One. 2013; 8:e71958.

63. Maher B. Personal genomes: the case of the missing heritability. Nature. 2008; 456:18–21.

64. Thomsen SF, van der Sluis S, Kyvik KO, Skytthe A, Backer V. Estimates of asthma heritability in a large twin sample. Clin Exp Allergy. 2010; 40:1054–1061.

65. Gibson G. Hints of hidden heritability in GWAS. Nat Genet. 2010; 42:558–560.

66. Janssens AC, Gwinn M, Subramonia-Iyer S, Khoury MJ. Does genetic testing really improve the prediction of future type 2 diabetes? PLoS Med. 2006; 3:e114.

67. McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JP, et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet. 2008; 9:356–369.

68. Igartua C, Myers RA, Mathias RA, Pino-Yanes M, Eng C, Graves PE, et al. Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma. Nat Commun. 2015; 6:5965.

69. Smith D, Helgason H, Sulem P, Bjornsdottir US, Lim AC, Sveinbjornsson G, et al. A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma. PLoS Genet. 2017; 13:e1006659.

70. Li JZ, Absher DM, Tang H, Southwick AM, Casto AM, Ramachandran S, et al. Worldwide human relationships inferred from genome-wide patterns of variation. Science. 2008; 319:1100–1104.

71. Shriner D, Adeyemo A, Gerry NP, Herbert A, Chen G, Doumatey A, et al. Transferability and fine-mapping of genome-wide associated loci for adult height across human populations. PLoS One. 2009; 4:e8398.

72. Baye TM, Butsch Kovacic M, Biagini Myers JM, Martin LJ, Lindsey M, Patterson TL, et al. Differences in candidate gene association between European ancestry and African American asthmatic children. PLoS One. 2011; 6:e16522.

73. Leung TF, Ko FW, Sy HY, Tsui SK, Wong GW. Differences in asthma genetics between Chinese and other populations. J Allergy Clin Immunol. 2014; 133:42–48.

74. Spencer CC, Su Z, Donnelly P, Marchini J. Designing genome-wide association studies: sample size, power, imputation, and the choice of genotyping chip. PLoS Genet. 2009; 5:e1000477.

75. LeCun Y, Bengio Y, Hinton G. Deep learning. Nature. 2015; 521:436–444.

76. Hancock DB, Romieu I, Shi M, Sienra-Monge JJ, Wu H, Chiu GY, et al. Genome-wide association study implicates chromosome 9q21.31 as a susceptibility locus for asthma in mexican children. PLoS Genet. 2009; 5:e1000623.

77. 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; 362:36–44.

78. Himes BE, Lasky-Su J, Wu AC, Wilk JB, Hunninghake GM, Klanderman B, et al. Asthma-susceptibility variants identified using probands in case-control and family-based analyses. BMC Med Genet. 2010; 11:122.

79. 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; 125:336–346.e4.

80. DeWan AT, Triche EW, Xu X, Hsu LI, Zhao C, Belanger K, et al. PDE11A associations with asthma: results of a genome-wide association scan. J Allergy Clin Immunol. 2010; 126:871–873.e9.

81. Ferreira MA, McRae AF, Medland SE, Nyholt DR, Gordon SD, Wright MJ, et al. Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia. Eur J Hum Genet. 2011; 19:458–464.

82. Ferreira MA, Matheson MC, Duffy DL, Marks GB, Hui J, Le Souëf P, et al. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet. 2011; 378:1006–1014.

83. Noguchi E, Sakamoto H, Hirota T, Ochiai K, Imoto Y, Sakashita M, et al. Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations. PLoS Genet. 2011; 7:e1002170.

84. 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; 43:893–896.

85. Lasky-Su J, Himes BE, Raby BA, Klanderman BJ, Sylvia JS, Lange C, et al. HLA-DQ strikes again: genome-wide association study further confirms HLA-DQ in the diagnosis of asthma among adults. Clin Exp Allergy. 2012; 42:1724–1733.

86. Li X, Ampleford EJ, Howard TD, Moore WC, Torgerson DG, Li H, et al. Genome-wide association studies of asthma indicate opposite immunopathogenesis direction from autoimmune diseases. J Allergy Clin Immunol. 2012; 130:861–868.e7.

87. Galanter JM, Gignoux CR, Torgerson DG, Roth LA, Eng C, Oh SS, et al. Genome-wide association study and admixture mapping identify different asthma-associated loci in Latinos: the Genes-environments & Admixture in Latino Americans study. J Allergy Clin Immunol. 2014; 134:295–305.

88. 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; 68:391–400.

89. Nieuwenhuis MA, Siedlinski M, van den Berge M, Granell R, Li X, Niens M, et al. Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma. Allergy. 2016; 71:1712–1720.

90. Barreto-Luis A, Pino-Yanes M, Corrales A, Campo P, Callero A, Acosta-Herrera M, et al. Genome-wide association study in Spanish identifies ADAM metallopeptidase with thrombospondin type 1 motif, 9 (ADAMTS9), as a novel asthma susceptibility gene. J Allergy Clin Immunol. 2016; 137:964–966.

91. Ramasamy A, Kuokkanen M, Vedantam S, Gajdos ZK, Couto Alves A, Lyon HN, et al. Genome-wide association studies of asthma in population-based cohorts confirm known and suggested loci and identify an additional association near HLA. PLoS One. 2012; 7:e44008.

92. 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; 49:1601505.