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

Abstract

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.

Keywords: Total serum IgE; asthma; atopic dermatitis; genome-wide association study; human leukocyte antigen; multiethnic.

Figure 1:. Clinical characteristics.

1A) Breakdown of ancestry, disease group and genotyping platform across studies. 1B) Barplot of the total serum IgE IU/ml geometric mean by study, stratified by allergic/non-allergic group, colored by ancestry.

Figure 2:. tIgE GWAS Manhattan plot.

Red dots denote loci previously reported by the tIgE GWAS, light blue dots denote loci not previously reported by tIgE GWAS, and pink dots denote the chr1q21 EDC and chr17q12–21 regions. Diamonds denote lead SNPs from previous GWAS. The red line denotes genome-wide significance (P=5×10⁻⁹), the blue line denotes suggestive significance (P=10⁻⁶).

Figure 3:. Locus zoom plots of tIgE and gene expression regions with evidence for co-localization.

3A) FCER1A (ENSG00000179639.10) in Adipose Visceral Omentum (PPH4=0.9986), 3B) IL13 (ENSG00000169194) in Testis (PPH4=0.9961), 3C) STAT6 (ENSG00000166888) in Cultured Fibroblasts (PPH4=0.9984).

Figure 4:. Associations in the HLA locus.

4A) Locus zoom plot. Lead variants in each peak are colored red. The red horizontal line denotes the 5×10⁻⁹ genome-wide significance threshold, the blue line denotes suggestive significance at 10⁻⁶. 4B) Linkage disequilibrium (r²) between lead variants in African (ASW), European (CEU) and Hispanic/Latino (MXL) 1000 Genomes populations.