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Wandering out of the GWAS wilderness: a new pathway paradigm for complex disease genetics
  1. Jeffrey Sturek,
  2. Imre Noth
  1. Division of Pulmonary and Critical Care, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA
  1. Correspondence to Dr Imre Noth, Division of Pulmonary and Critical Care, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; IN2C{at}hscmail.mcc.virginia.edu

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A genetic contribution to asthma susceptibility has long been recognised.1 Despite multiple approaches, from candidate genes to genome-wide association studies (GWAS), a large proportion of this heritability remains unexplained.2 The reasons for this are myriad and are largely generalisable to similar approaches in other complex diseases and phenotypes. Candidate gene studies are well based in known pathophysiology and can be powered to identify small effect sizes, but often provide limited insight into new biology or therapeutic opportunities. GWAS are largely unbiased (tagging single-nucleotide polymorphism (SNP) selection not withstanding) and provide opportunities for discovery, but identifying the biologically functional variant can prove daunting, and other important variants likely do not survive genome-wide significance corrections where sample sizes, and hence statistical power, are limited. Both of these approaches in isolation are also likely to miss the influence of genetics on the complex phenotypic response to environmental exposures. In this issue of Thorax, Dizier et al report an interesting pathway-based approach to a gene by environment (G×E) analysis of a well-established epidemiological association between environmental tobacco smoke (ETS) exposure and bronchial hyper-responsiveness (BHR).3 This hybrid method has some of the benefits of multiple modalities and may provide a new avenue for further clarifying the genetic underpinnings of other complex diseases.

The basis for the current study …

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