RATIONALE: Total serum IgE (tIgE) is an important mediator of allergic disease. tIgE is highly elevated in atopic diseases such as asthma, rhinitis, conjunctivitis, atopic dermatitis and food allergy, and elevated tIgE is associated with coronary artery disease. tIgE is an important intermediary phenotype of asthma, and has a higher heritability than asthma; with heritability estimates ranging between 40-80%. In order to better understand risk factors for atopy in the context of asthma, we performed a multi-ethnic whole genome meta-analysis of tIgE using TOPMed sequence data.
METHODS: Data from Barbados Asthma Genetics Study, The Genetic Epidemiology of Asthma in Costa Rica and the Childhood Asthma Management Program, Severe Asthma Research Program and Framingham Heart Study (FHS) were included in our meta-analysis. Analysis strata were defined based on study, race/ethnicity and asthma status (n=6,104 total, n=1,352 African ancestry, n=4,571 European ancestry, n=2,117 asthmatics). Linear mixed effect models (which allows for adjustment of relatedness) was run through the ENCORE web server using TOPMed freeze6a data (SAIGE software) separately for each stratum. Results were combined using inverse-variance meta-analysis.
RESULTS: We confirmed four of the five genome-wide associations previously reported (P≤10-5, FCER1A, IL13, MHC class II and STAT6 gene loci). SNPs in the vicinity of STAT6 achieved genome-wide significance (P≤5×10-8). This region also achieved genome-wide significance in the previous FHS GWAS of tIgE. STAT6 is a transcription factor that affects Th2 lymphocyte responses mediated by IL-4 and IL-13, and has been identified by genome-wide association studies (GWAS) of asthma performed by the Trans-National Asthma Genetic Consortium (TAGC) and the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA). Two novel loci with suggestive associations (P≤10-6) not previously reported by GWAS of tIgE were located in the vicinity of the genes LRRC32+GUCY2EP and RIMBP2+STX2, respectively. LRRC32 has previously been reported by a GWAS of atopic dermatitis.
FUTURE WORK: Our next steps are to include additional TOPMed studies with available tIgE data (Genetic Epidemiology of COPD and Genetics of Cardiometabolic Health in the Amish) in the meta-analysis and genotype array data from other sources (CAAPA, Genetics of Asthma Susceptibility to Pollution, Atopic Dermatitis Research Network) imputed using the TOPMed reference panel.

Introduction Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV1), is one of the standard diagnostic criterion used by pulmonary clinicians to identify and classify lung diseases. FEV1 is strongly influenced by genetics, with heritability estimates as high as 55%. Specifically, numerous genetic loci associated with FEV1 have been identified, and there is also evidence that genetic ancestry plays a role in FEV1 variation. Several epidemiological studies have identified early-life exposure to air pollution as a significant predictor of baseline lung function. Although there have been numerous genetic and epidemiological studies aimed at identifying the genetic and environmental factors responsible for variation in FEV1, the majority of the heritability remains undefined. FEV1 is a complex phenotype that has been shown to be heavily influenced by both environmental and genetic factors. We hypothesize that a portion of the “hidden heritability” for FEV1 may be explained by gene-by-environment (GxE) interactions.
Methods We performed whole genome sequencing on 1,133 Puerto Rican children with asthma and available early-life exposure to air pollution data. We then constructed multiplicative interaction models (single nucleotide polymorphism [SNP] x air pollution). We then performed a GWIS (genome-wide interaction study) to test the effect of each interaction model on variation in FEV1. All regression models were adjusted for age, sex, global ancestry, and the main effects of the specified SNP and air pollution.

Results and Conclusions We identified several GxE interactions associated with FEV1 in Puerto Rican children with asthma. Our preliminary results indicate that GxE interactions play an important role in FEV1 variation in this population.

Asthma is a complex disease with striking disparities between ethnicities, and asthmatics of African descent have more severe asthma, poorer response to therapy, and higher IgE levels compared to asthmatics of European ancestry. Genetics of asthma research has been conducted in the Barbados Asthma Genetics Study (BAGS) for >2 decades focused on a population of African descent. As part of the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) Program, high coverage whole genome sequencing (WGS; 39.4 average depth) was performed on samples collected from 190 families (mean pedigree size of 5.7 individuals, ranging from 1 to 56 individuals). Sequencing was 99.5% concordant with samples genotyped on the Illumina OMNI 2.5 array. The average Yoruba (YRI) component in Barbados is 88%. There were 41.9 million (M) variants observed, of which 6.3M (15%) were private. 59.8% (~25.1M) with an minor allele frequency (MAF) ≤1%, 17.2% (~7.2M) with a MAF 1-5%, and only 23.0% (~9.6M) were common ( MAF>5%). On average, individuals had 4.3M variants different from reference (NCBI37), of which 1.6M (38.4%) were in genes, and ~24,000 (0.6%) were coding. This data set provides us with the opportunity to investigate the role that structural and rare variants may have in allergic disease and asthma. To illustrate the utility of the data set and to hone in on rare variation associated with disease, we examined one of the largest and well-characterized pedigrees of 31 individuals to determine how private variants may play a role in asthma pathogenesis. Among 226,498 variants private to this family, a novel missense variant predicted to be damaging by both polyphen2 and SIFT in the ADAMTS12 gene, a gene previously associated with asthma in linkage studies, is found in 15 of 31 individuals in this family. We discuss our quality control and analysis pipeline and showcase preliminary results.