A Review of Asthma GWAS Reviews

 

Since 2007, over 44 asthma and related trait GWAS have been published, while at the same time, over 28 asthma GWAS reviews have been published. Although most reviews include novel insights or give a unique perspective, there seems to be an unnecessarily large number of asthma GWAS reviews. Here, I offer a review of these reviews for someone who would like to quickly become familiar with the asthma GWAS literature. Asthma shares features with other allergic diseases, and there are various physiological measures that are usually characteristic of asthma but also differ considerably among asthma patients and may be present in individuals who do not have asthma. Some asthma-related traits include blood eosinophil count, total serum and specific IgE levels, lung function measures, allergic rhinitis, and atopic dermatitis. Most asthma GWAS reviews include studies of these asthma-related phenotypes because understanding them may offer clues about shared biological mechanisms.

The short answer is that the most comprehensive and inclusive review is [1]. Start there! Even though it is a bit old, it captures most of the major asthma GWAS conducted to date and provides details on both the phenotypes captured and gene association methods. It is sparse on details for each study mentioned, but because it has 281 references, you can easily follow-up on any particular topic of interest.

Other general reviews focused primarily on asthma published since 2011 include: [2][3][4][5][6][7][8][9][10]. One paper includes a nice Venn diagram of overlapping gene-level associations with various phenotypes. Some reviews include asthma pharmacogenetic phenotypes, especially bronchodilator response and inhaled corticosteroid responsiveness, which have been most widely studied [5][11].

One of the asthma-related traits that has been comprehensively reviewed on its own is IgE levels [12]. The IgE antiobody class is involved in allergic response and its levels are altered in many diseases, including asthma. Various GWAS studies have been conducted to identify genetic loci associated with baseline IgE levels among patients with asthma as well as persons with no allergic diseases. The overlap between GWAS hits for asthma and IgE levels is so far limited to a few regions (e.g. RAD50 and HLA-DRB1), suggesting that the genetic predisposition to asthma is mostly independent to that of IgE levels. Thus, the high IgE levels observed in asthma patients may be due to physiological effects that occur after asthma has developed.

Severe asthma, defined as asthma whose symptoms and exacerbations remain despite treatment with medications, has also been studied on its own and as a sub-phenotype within other asthma GWAS studies [13]. The major associations measured with this phenotype are in loci near RAD50/IL13, TSLP, and HLA-DQB1, but study of this phenotype has been hampered by the small sample sizes of available cohorts so far. A more recent severe asthma GWAS study not covered in the review is [14]. This study found known loci (GSDMB, IL33, RAD50 and IL1RL1) and identified CDHR3 as a novel locus.

A review focused on age of asthma onset noted that there still is no way to conclusively diagnose asthma in children, including via genetic/genomic approaches. While the most strongly replicated asthma GWAS locus (ORMDL3) seems to be specific to childhood asthma, and other loci have been reported to be associated with age of asthma onset (e.g. IL5RA), GWAS results have not been translated into biological knowledge that helps explain which children suffer asthma and why [15].

 

Asthma_GRASP106_Phenogram
Asthma-associated genes as reported in GRASP (p<10^-6) and visualized with PhenoGram. Number in parentheses denotes number of separate published papers that report association with SNP(s) in/near the given gene. The absence of X chromosome-associated genes may be due to exclusion of this chromosome from most asthma GWAS.

References

  1. C. Ober, and T. Yao, "The genetics of asthma and allergic disease: a 21st century perspective.", Immunological reviews, 2011. http://www.ncbi.nlm.nih.gov/pubmed/21682736
  2. M. Tamari, S. Tanaka, and T. Hirota, "Genome-wide association studies of allergic diseases.", Allergology international : official journal of the Japanese Society of Allergology, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23439055
  3. M. Wjst, M. Sargurupremraj, and M. Arnold, "Genome-wide association studies in asthma: what they really told us about pathogenesis.", Current opinion in allergy and clinical immunology, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23222155
  4. R.E. Slager, G.A. Hawkins, X. Li, D.S. Postma, D.A. Meyers, and E.R. Bleecker, "Genetics of asthma susceptibility and severity.", Clinics in chest medicine, 2012. http://www.ncbi.nlm.nih.gov/pubmed/22929093
  5. A. Binia, and M. Kabesch, "Respiratory medicine - genetic base for allergy and asthma.", Swiss medical weekly, 2012. http://www.ncbi.nlm.nih.gov/pubmed/22915201
  6. J.L. Todd, D.B. Goldstein, D. Ge, J. Christie, and S.M. Palmer, "The state of genome-wide association studies in pulmonary disease: a new perspective.", American journal of respiratory and critical care medicine, 2011. http://www.ncbi.nlm.nih.gov/pubmed/21799071
  7. M. Tamari, K. Tomita, and T. Hirota, "Genome-wide association studies of asthma.", Allergology international : official journal of the Japanese Society of Allergology, 2011. http://www.ncbi.nlm.nih.gov/pubmed/21681015
  8. W.O.C. Cookson, and M.F. Moffatt, "Genetics of complex airway disease.", Proceedings of the American Thoracic Society, 2011. http://www.ncbi.nlm.nih.gov/pubmed/21543792
  9. K.C. Barnes, "Genetic studies of the etiology of asthma.", Proceedings of the American Thoracic Society, 2011. http://www.ncbi.nlm.nih.gov/pubmed/21543791
  10. L. Akhabir, and A.J. Sandford, "Genome-wide association studies for discovery of genes involved in asthma.", Respirology (Carlton, Vic.), 2011. http://www.ncbi.nlm.nih.gov/pubmed/21276132
  11. S.T. Weiss, "New approaches to personalized medicine for asthma: where are we?", The Journal of allergy and clinical immunology, 2012. http://www.ncbi.nlm.nih.gov/pubmed/22284929
  12. D.P. Potaczek, and M. Kabesch, "Current concepts of IgE regulation and impact of genetic determinants.", Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2012. http://www.ncbi.nlm.nih.gov/pubmed/22909159
  13. E. Melén, and G. Pershagen, "Pathophysiology of asthma: lessons from genetic research with particular focus on severe asthma.", Journal of internal medicine, 2012. http://www.ncbi.nlm.nih.gov/pubmed/22632610
  14. K. Bønnelykke, P. Sleiman, K. Nielsen, E. Kreiner-Møller, J.M. Mercader, D. Belgrave, H.T. den Dekker, A. Husby, A. Sevelsted, G. Faura-Tellez, L.J. Mortensen, L. Paternoster, R. Flaaten, A. Mølgaard, D.E. Smart, P.F. Thomsen, M.A. Rasmussen, S. Bonàs-Guarch, C. Holst, E.A. Nohr, R. Yadav, M.E. March, T. Blicher, P.M. Lackie, V.W.V. Jaddoe, A. Simpson, J.W. Holloway, L. Duijts, A. Custovic, D.E. Davies, D. Torrents, R. Gupta, M.V. Hollegaard, D.M. Hougaard, H. Hakonarson, and H. Bisgaard, "A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations.", Nature genetics, 2013. http://www.ncbi.nlm.nih.gov/pubmed/24241537
  15. F.N. Dijk, J.C. de Jongste, D.S. Postma, and G.H. Koppelman, "Genetics of onset of asthma", Current Opinion in Allergy and Clinical Immunology, vol. 13, pp. 193-202, 2013. http://dx.doi.org/10.1097/ACI.0b013e32835eb707