Asthma and the Missing Heritability Problem: Necessity for Multiomics Approaches in Determining Accurate Risk Profiles

Abstract

Asthma is ranked among the most common chronic conditions and has become a significant public health issue due to the recent and rapid increase in its prevalence. Investigations into the underlying genetic factors predict a heritable component for its incidence, estimated between 35% and 90% of causation. Despite the application of large-scale genome-wide association studies (GWAS) and admixture mapping approaches, the proportion of variants identified accounts for less than 15% of the observed heritability of the disease. The discrepancy between the predicted heritable component of disease and the proportion of heritability mapped to the currently identified susceptibility loci has been termed the 'missing heritability problem.' Here, we examine recent studies involving both the analysis of genetically encoded features that contribute to asthma and also the role of non-encoded heritable characteristics, including epigenetic, environmental, and developmental aspects of disease. The importance of vertical maternal microbiome transfer and the influence of maternal immune factors on fetal conditioning in the inheritance of disease are also discussed. In order to highlight the broad array of biological inputs that contribute to the sum of heritable risk factors associated with allergic disease incidence that, together, contribute to the induction of a pro-atopic state. Currently, there is a need to develop in-depth models of asthma risk factors to overcome the limitations encountered in the interpretation of GWAS results in isolation, which have resulted in the missing heritability problem. Hence, multiomics analyses need to be established considering genetic, epigenetic, and functional data to create a true systems biology-based approach for analyzing the regulatory pathways that underlie the inheritance of asthma and to develop accurate risk profiles for disease.

Keywords: GWAS - genome-wide association study; asthma; epigenetics; inheritability; maternal inheritance, atopic disease; microbiome and dysbiosis; multiomics approach.

Figure 1

Summary of the Heritable Genetic and Non-Genetic Factors that Contribute to the Predisposition for Atopic Diseases. Factors can be divided into two major categories. (1) Genetic factors including genetically encoded features such as SNPs and HLA haplotype, along with alterable non-genetically encoded epigenetic features including DNA methylation and histone acetylation status. (2) Non-Genetic factors consisting of developmental, environmental, and maternal influences including the maternal microbiome is all transmitted during fetal and/or early neonatal development.

Figure 2

Mechanisms of Allergic Disease Development. (A) Representative image depicting the first stage of an allergic response driven by the recognition of environmental allergens as inflammatory mediators by pattern recognition receptors (PRR) present on the surface of dendritic cells (DC) and epithelial cells in barrier tissues. Epithelial cells produce defensive cytokines including TSLP, IL-25 and IL-33 that modulate activated DC and direct naïve T cells towards the TH2 phenotype. In the absence of inflammatory stimuli, naïve T cells may be activated in a tolerogenic manner and differentiate to become peripherally induced Treg cells (pTreg), which in concert with thymically produced T regs (nTreg), mediate the dampening of inflammatory responses. Activated TH2 cells produce IL-4 and mediate B cell class switching and production of IgE. Together with ILC2, Th2 cells additionally produce IL-5 and IL-13 that regulate the activation of the innate immune system and induces migration of eosinophils, mast cells and basophils to the sites of inflammation, where IgE bound to the FcERI receptors on mast cells and basophils recognizes the cognate allergen. This induces degranulation and release of further inflammatory mediators including histamine, leukotrienes, and heparin. (B) Analysis of protein-protein interactions of the 216 genes identified by GWAS from Han et al. (19) using the STRING database (48). Identification of several clusters of highly relevant pathways that overlay with the known functional pathways previously associated with asthma and allergic diseases, including the major cytokines signals associated with TH2 differentiation (IL-2, IL-4 and IL-13) along with the downstream mediators of differentiation—STAT6 and GATA3—and transcription factors associated with Treg differentiation—FOXP1 and SMAD—which are involved in the TGFβ signaling (blue). Additionally, the TRAF1 signaling nexus is identified, where TRAF1 has previously been identified as a key factor in allergic inflammation and the regulation of IL-4 production (red) (49). FcERI signaling and interactions between TCR and MHCII (HLA-DQA1) are identified (green) and multiple pairs of protein-protein interactions integral for development of allergic inflammation are also identified (pink)—notably IL-33-IL1RL1 (50) and BATF3-BACH2 (51). Data displayed is developed using Cytoscape v.3.9 (52).