Background-Childhood and adult onset asthma differ with respect to severity and comorbidities. Whether they also differ with respect to genetic risk factors has not been previously investigated in large samples. The goals of this study were to identify shared and distinct genetic risk loci for childhood and adult onset asthma, and the genes that may mediate the effects of associated variation.Methods-We used data from UK Biobank to conduct genome-wide association studies (GWASs) in 37,846 subjects with asthma, including 9,433 childhood onset cases (onset before age 12) and 21,564 adult onset cases (onset between ages 26 and 65), and 318,237 subjects without asthma (controls; older than age 38). We conducted GWASs for childhood onset asthma and adult onset asthma each compared to shared controls, and for age of asthma onset in all 37,846 asthma cases. Enrichment studies determined the tissues in which genes at GWAS loci were most highly expressed, and PrediXcan, a transcriptome-wide gene-based test, was used to identify candidate risk genes.Findings-We detected 61 independent asthma loci: 23 were childhood onset specific, one was adult onset specific, and 37 were shared. Nineteen loci were associated with age of asthma onset.

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Chromosome 17q12–21 remains the most highly replicated and significant asthma locus. Genotypes in the core region defined by the first genome-wide association study correlate with expression of 2 genes, ORM1-like 3 (ORMDL3) and gasdermin B (GSDMB), making these prime candidate asthma genes, although recent studies have implicated gasdermin A (GSDMA) distal to and post-GPI attachment to proteins 3 (PGAP3) proximal to the core region as independent loci. We review 10 years of studies on the 17q12–21 locus and suggest that genotype-specific risks for asthma at the proximal and distal loci are not specific to early-onset asthma and mediated by PGAP3, ORMDL3, and/or GSDMA expression. We propose that the weak and inconsistent associations of 17q single nucleotide polymorphisms with asthma in African Americans is due to the high frequency of some 17q alleles, the breakdown of linkage disequilibrium on African-derived chromosomes, and possibly different early-life asthma endotypes in these children. Finally, the inconsistent association between asthma and gene expression levels in blood or lung cells from older children and adults suggests that genotype effects may mediate asthma risk or protection during critical developmental windows and/or in response to relevant exposures in early life. Thus studies of young children and ethnically diverse populations are required to fully understand the relationship between genotype and asthma phenotype and the gene regulatory architecture at this locus. (J Allergy Clin Immunol 2018;142:749–64.)

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.

This review focuses on genome-wide association studies (GWASs) of asthma and allergic diseases published between January 1, 2018, and June 30, 2019. During this time period, there were 38 GWASs reported in 19 articles, including the largest performed to date for many of these conditions. Overall, we learned that childhood-onset asthma is associated with the most independent loci compared with other defined groups of asthma and allergic disease cases; adult-onset asthma and moderate-to-severe asthma are associated with fewer genes, which are largely a subset of those associated with childhoodonset asthma. There is significant genetic overlap between asthma and allergic diseases, particularly with respect to childhood-onset asthma, which involves genes that reflect the importance of barrier function biology, and to HLA region genes, which are the most frequently associated genes overall in both groups of diseases. Although the largest GWASs in African American and Latino/Hispanic populations were reported during this period, they are still significantly underpowered compared with studies reported in populations of European ancestry, highlighting the need for larger studies, particularly in patients with childhood-onset asthma and allergic diseases, in these important populations that carry the greatest burden of disease.