title: Genome-wide association studies in asthma:  what they really told us about pathogenesis.
abstract: OBJECTIVE
  Over the past years, several consortia have provided a data deluge from large-scale, genome-wide association studies (GWASs) for numerous asthma and allergy related traits. Dozens of reviews have already summarized the main results, although a coherent picture is still missing, referred to as 'missing' or 'unexplained' heritability.
  
  
  RESULTS
  We identify the factors responsible for the unexplained heritability including imprecise phenotyping, biased single-nucleotide polymorphism selection (preferentially gene-based and high allele frequency with poor linkage disequilibrium tagging capacity), heterogeneity and insufficient significance ranking test statistics. In spite of these problems, three major outcomes can already be identified. First, rare variants give the highest risk estimates but are limited to small subgroups indicating a complex origin of asthma that may involve hundreds of variants that are either population, family or individual specific. Second, only a few common variants are shared amongst all asthmatics where the IL33/ST2 pathway turns out to be the most relevant factor. Third, transcription factor binding sites are enriched amongst the top association results pointing towards disturbed regulatory network function in asthma.
  
  
  CONCLUSIONS
  The next wave of asthma genetic studies will use full-genome sequencing and overcome most GWAS-associated problems. It will be the last step of a century-long search for asthma genes, satisfying scientific curiosity and, hopefully, also providing data applicable in translational medicine.
authors.affiliation: Comprehensive Pneumology Center, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany. wjst@helmholtz-muenchen.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Wjst
authors.forename: Muralidharan
authors.initials: M
authors.lastname: Sargurupremraj
authors.forename: Matthias
authors.initials: M
authors.lastname: Arnold
mesh_terms: D001249:Asthma / Q000209:etiology / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000502:physiology; D057170:Translational Research, Biomedical
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D011956:Receptors, Cell Surface; C079241:IL1RL1 protein, human; C506536:IL33 protein, human; C407909:TCF3 protein, human