African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans

BACKGROUND: Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry. METHODS: We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American-specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults. RESULTS: Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma. CONCLUSIONS: Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases

Additional file 1 of African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans

Additional file 1. Contains Supplementary Methods, Supplementary Tables (Table S1-10), and Supplementary Figures (Fig. S1-14), and corresponding references. Supplementary Methods. Descriptions of Populations. Building Consensus Sequences in the Critical Region. Table S1. Characteristics of the APIC and URECA Cohorts. Table S2. Predicted Haplotypes in CREW. Table S3. Haplotype Frequencies in Whole Genome Sequences. Table S4. Worldwide Frequencies of African-specific SNPs. Table S5. cis-eQTL Results for SNPs in or near GSDMA. Table S6. ENCODE Cell Lines and DNAse Clustering at pcHi-C Region. Table S7. pcHi-C Target Genes for African-specific Variants in Airway Epithelial Cells. Table S8. pcHi-C Target Genes for African-specific Variants in Airway Immune Cells. Table S9. Quantitative Trait Association Results in the APIC and URECA Cohorts. Table S10. African American Adult Asthmatics by Severity and Genotype. Figure S1. Overview of Study Design. Figure S2. ChromoPainter Analysis. Figure S3. ChromoPainter Visualization of Haplotype Breakpoints. Figure S4. ChromoPainter Display of the 17q12-q21 Region in Haplotype 4 Homozygotes. Figure S5. Ancestry PCA plots for APIC and URECA Children. Figure S6. eQTL Box Plots of rs28623237 Genotype and GSDMA Expression in CAAPA2. Figure S7. LD Plot of African-specific Variants and SNPs in or near GSDMA. Figure S8. eQTL Box Plots of rs113282230 Genotype and GSDMA Expression Conditioned on GSDMA SNPs. Figure S9. eQTL Violin Plots of rs235480 and rs1132828830 Genotypes on GSDMA and GSDMB Expression. Figure S10. LD Plot of the African-specific Variants and SNPs in the Core Region of The 17q12-q21 Locus. Figure S11. Chromatin Annotations in the Region Encoding the African-specific SNPs in ENCODE Cell Lines. Figure S12. eGenes for rs113282230 in Immune Cells. Figure S13. pcHi-C Data for rs113282230 in Immune Cells. Figure S14. Rs113282230 Genotype Effect on Asthma Prevalence by rs2305480 AA And GG Genotypes in APIC and URECA

Additional file 2 of African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans

Additional file 2. Region-wide eQTL results in airway epithelial cells from 189 African American children in the URECA cohort

Expression quantitative trait locus fine mapping of the 17q12–21 asthma locus in African American children: a genetic association and gene expression study

Background: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12–21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12–21 locus. Methods: We first did a genetic association study and meta-analysis using 17q12–21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12–21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12–21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). Findings: 17q12–21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p<0·0055 (for rs2305480_G, odds ratio [OR] 1·36 [95% CI 1·12–1·65], p=0·0014; and for rs8076131_A, OR 1·37 [1·13–1·67], p=0·0010). In upper airway epithelial cells from African American children, genotype at rs2305480 was the most significant eQTL for GSDMB (eQTL effect size [β] 1·35 [95% CI 1·25–1·46], p<0·0001), and to a lesser extent showed an eQTL effect for post-GPI attachment to proteins phospholipase 3 (β 1·15 [1·08–1·22], p<0·0001). No SNPs were eQTLs for ORMDL3. By contrast, in PBMCs, the five core SNPs were associated only with expression of GSDMB and ORMDL3. Genotype at rs12936231 (in zona pellucida binding protein 2) showed the strongest associations across both genes (for GSDMB, eQTLβ 1·24 [1·15–1·32], p<0·0001; and for ORMDL3 (β 1·19 [1·12–1·24], p<0·0001). The eQTL effects of rs2305480 on GSDMB expression were replicated in lower airway cells from African American adults (β 1·29 [1·15–1·44], p<0·0001). Interpretation: Our study suggests that SNPs regulating GSDMB expression in airway epithelial cells have a major role in childhood-onset asthma, whereas SNPs regulating the expression levels of 17q12–21 genes in resting blood cells are not central to asthma risk. Our genetic and gene expression data in African Americans and European Americans indicated GSDMB to be the leading candidate gene at this important asthma locus.6 month embargo; published: 01 May 2020This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]