Whole genome sequencing association and gene-by-air-pollution interaction analyses identified kitlg as a novel baseline lung function gene candidate among African American children with asthma
Mak A, Sajuthi S, Saef B, Hu D, Xiao S, Sleiman P, Joo J, Lee EY, Huntsman S, Eng C, LeNoir MA, Brigino-Buenaventura E, Salazar S, Oh SS, Himes BE, Hakonarson H, Williams L, White MJ, Seibold MA, and Burchard EG. Whole genome sequencing association and gene-by-air-pollution interaction analyses identified kitlg as a novel baseline lung function gene candidate among African American children with asthma. American Journal of Respiratory and Critical Care Medicine 2020; 201(1).
American Journal of Respiratory and Critical Care Medicine
RATIONALE: Baseline lung function, quantified as the forced expiratory volume in the first second of exhalation (FEV1), is a standard diagnostic criterion used by clinicians to identify and classify lung diseases. FEV1 is a complex phenotype that is heavily influenced by both environmental and genetic factors, with estimated heritability as high as 55%. Epidemiological studies have shown that early-life exposure to air pollution is a significant predictor of baseline lung function, while several genetic loci have been associated with FEV1 and genetic ancestry contributes to its variation. Despite numerous studies linking genetic and environmental factors to variation in FEV1, the majority of its heritability remains unexplained. We hypothesized that a portion of this missing heritability is due to gene-by-environment (GxE) interactions.
METHODS: Using whole genome sequencing data on 876 African American children with asthma from the Trans-Omics for Precision Medicine (TOPMed) program, we performed a genome-wide association study of FEV1 using the ENCORE tool. Potential gene targets of associated variants were identified using long range chromatin interaction data available in the HUGIN browser. RNA-Seq data of nasal epithelial cells from minority children with asthma was used to identify eQTLs of potential gene targets. FEV1-associated variants were overlapped with candidate cisregulatory elements (ccRE) from ENCODE to identify variants with potential regulatory function. Gene-by-air pollution analyses using early-life and past-year exposure to air pollution were performed. All models were adjusted for age, sex, height, the first five genetic principal components, use of controller medications and sequencing batches.
RESULTS AND CONCLUSION: We identified a novel genome-wide significant locus on chromosome 12 (rs73429450) that was associated with FEV1 (p = 1.26 x 10-8, β =0.302). Publicly available Hi-C and in-house eQTL data supported a regulatory role of the novel locus on the KITLG gene. Additional gene-by-air-pollution interaction analyses found that candidate variants interacted with SO2 in the first year of life (rs73440122, p = 0.049, β = 0.009) and past-year exposure (rs58475486, p = 0.003, β = 0.539) to modify association with FEV1. Thus, we identified KITLG as a novel gene candidate with variants that have protective genetic association and gene-by-SO2 interactions with baseline lung function (FEV1) among African American children with asthma.