Multiethnic genome-wide and HLA association study of total serum IgE level

Background: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. Objective: We aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N = 21,901). Methods: We performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. Results: We identified 6 loci at genome-wide significance (P < 5 × 10^–9), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (P_discovery = 2 × 10^–4; P_replication = 5 × 10^–4; P_{discovery+replication} = 4 × 10^–7), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (P_{Hispanic/Latino discovery+replication} = 8 × 10^–8). Conclusion: We performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.