Asthma Genetics in the Post-GWAS Era

Abstract

Genome-wide association studies (GWAS) of asthma have yielded exciting results and identified novel risk alleles and loci. But, like other common complex diseases, asthma-associated alleles have small effect sizes and account for little of the prevalence of asthma. In this review, I discuss the limitations of GWAS approaches and the major challenges facing geneticists in the post-GWAS era and propose alternative strategies to address these challenges. In particular, I propose that focusing on genetic variations that influences gene expression and using cell models of gene-environment interactions in cell types that are relevant to asthma will allow us to more completely characterize the genetic architecture of asthma.

Keywords: asthma; epigenomics; gene-environment interaction; genetic variation; quantitative trait loci.

Figure 1.

Overview of results of genome-wide association studies (GWAS) for asthma. Figure is shown as a stylized inverted Manhattan plot, which was created on the basis of published data. Colors represent different autosomal chromosomes (1–22, left to right). Many asthma-associated loci have been discovered by GWAS. These associations are generally robust across ethnic and racial groups and represent the “low-hanging fruit” (shown as apples). However, separating signal from noise among the variants with small P values that do not reach the genome-wide criteria for significance (i.e., the “mid-hanging fruit” among the branches, not shown) remains challenging. These loci likely include many exposure-specific associations and may be validated using cell culture models of gene–environment interactions. Figure drawn by S. Mozaffari.