Diversity and the Splice of Life: Mapping the 17q12-21.1 Locus for Variants Associated with Early-Onset Asthma in African American Individuals.
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ABSTRACT:
SUBMITTER: Raby BA
PROVIDER: S-EPMC7885835 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Rationale: The 17q12-21.1 locus is one of the most highly replicated genetic associations with asthma. Individuals of African descent have lower linkage disequilibrium in this region, which could facilitate identifying causal variants.Objectives: To identify functional variants at 17q12-21.1 associated with early-onset asthma among African American individuals.Methods: We evaluated African American participants from SAPPHIRE (Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity) (n = 1,940), SAGE II (Study of African Americans, Asthma, Genes and Environment) (n = 885), and GCPD-A (Study of the Genetic Causes of Complex Pediatric Disorders-Asthma) (n = 2,805). Associations with asthma onset at ages under 5 years were meta-analyzed across cohorts. The lead signal was reevaluated considering haplotypes informed by genetic ancestry (i.e., African vs. European). Both an expression-quantitative trait locus analysis and a phenome-wide association study were performed on the lead variant.Measurements and Main Results: The meta-analyzed results from SAPPHIRE, SAGE II, and the GCPD-A identified rs11078928 as the top association for early-onset asthma. A haplotype analysis suggested that the asthma association partitioned most closely with the rs11078928 genotype. Genetic ancestry did not appear to influence the effect of this variant. In the expression-quantitative trait locus analysis, rs11078928 was related to alternative splicing of GSDMB (gasdermin-B) transcripts. The phenome-wide association study of rs11078928 suggested that this variant was predominantly associated with asthma and asthma-associated symptoms.Conclusions: A splice-acceptor polymorphism appears to be a causal variant for asthma at the 17q12-21.1 locus. This variant appears to have the same magnitude of effect in individuals of African and European descent.
| S-EPMC7885840 | biostudies-literature
Project description:BackgroundAfrican 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.MethodsWe 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).Findings17q12-21 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).InterpretationOur 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.FundingNational Institutes of Health, Office of the Director.
| S-EPMC7335429 | biostudies-literature
Project description:BackgroundAsthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry.MethodsWe 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.ResultsOur 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.ConclusionsPreviously 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.
| S-EPMC9520885 | biostudies-literature
Project description:Some evidence suggests that depression may increase the risk of adult-onset asthma. No data are available for African American women, in whom the prevalence of depression and asthma is high.To conduct prospective analyses of the relation of depressive symptoms to asthma incidence in the Black Women's Health Study, a prospective cohort of US black women followed since 1995 with mailed biennial questionnaires.Of 31,848 participants followed from 1999 to 2011, 771 reported incident asthma. Depressive symptoms were ascertained on 1999 and 2005 follow-up questionnaires with the Center for Epidemiological Studies-Depression Scale (CES-D). Participants rated the frequency of 20 symptoms. A score was calculated by summing the responses to all questions. Cox regression models were used to derive incidence rate ratios and 95% confidence intervals for 4 categories of the CES-D score in relation to incident asthma, adjusted for body mass index, smoking, and other covariates.The multivariable incidence rate ratio in the highest category of CES-D score (? 33) compared with the lowest (<16) was 2.08 (95% confidence interval 1.58-2.74), with a significant trend (P < .0001). The incidence rate ratio was higher in women who took antidepressants, were current or former smokers, were not obese, and were at least 40 years old, although there were no statistically significant interactions.A positive association was observed between CES-D score and the incidence of adult-onset asthma. If the hypothesis is confirmed, depression could contribute substantially to the burden of asthma in adults.
| S-EPMC3972352 | biostudies-literature
Project description: Not available
| S-EPMC8277824 | biostudies-literature
Project description:Asthma originates from genetic and environmental factors with about half the risk of disease attributable to heritable causes. Genome-wide association studies, mostly in populations of European ancestry, have identified numerous asthma-associated single nucleotide polymorphisms (SNPs). Studies in populations with diverse ancestries allow both for identification of robust associations that replicate across ethnic groups and for improved resolution of associated loci due to different patterns of linkage disequilibrium between ethnic groups. Here we report on an analysis of 745 African-American subjects with asthma and 3,238 African-American control subjects from the Candidate Gene Association Resource (CARe) Consortium, including analysis of SNPs imputed using 1,000 Genomes reference panels and adjustment for local ancestry. We show strong evidence that variation near RAD50/IL13, implicated in studies of European ancestry individuals, replicates in individuals largely of African ancestry. Fine mapping in African ancestry populations also refined the variants of interest for this association. We also provide strong or nominal evidence of replication at loci near ORMDL3/GSDMB, IL1RL1/IL18R1, and 10p14, all previously associated with asthma in European or Japanese populations, but not at the PYHIN1 locus previously reported in studies of African-American samples. These results improve the understanding of asthma genetics and further demonstrate the utility of genetic studies in populations other than those of largely European ancestry.
| S-EPMC3975655 | biostudies-literature
Project description:A whole-genome admixture scan in 1,597 African Americans identified a 3.8 Mb interval on chromosome 8q24 as significantly associated with susceptibility to prostate cancer [logarithm of odds (LOD) = 7.1]. The increased risk because of inheriting African ancestry is greater in men diagnosed before 72 years of age (P < 0.00032) and may contribute to the epidemiological observation that the higher risk for prostate cancer in African Americans is greatest in younger men (and attenuates with older age). The same region was recently identified through linkage analysis of prostate cancer, followed by fine-mapping. We strongly replicated this association (P < 4.2 x 10(-9)) but find that the previously described alleles do not explain more than a fraction of the admixture signal. Thus, admixture mapping indicates a major, still-unidentified risk gene for prostate cancer at 8q24, motivating intense work to find it.
| S-EPMC1599913 | biostudies-literature
Project description:Chromosome 17q12-21 remains the most highly replicated and significant asthma locus. Genotypes in the core region defined by the first genome-wide association study correlate with expression of 2 genes, ORM1-like 3 (ORMDL3) and gasdermin B (GSDMB), making these prime candidate asthma genes, although recent studies have implicated gasdermin A (GSDMA) distal to and post-GPI attachment to proteins 3 (PGAP3) proximal to the core region as independent loci. We review 10 years of studies on the 17q12-21 locus and suggest that genotype-specific risks for asthma at the proximal and distal loci are not specific to early-onset asthma and mediated by PGAP3, ORMDL3, and/or GSDMA expression. We propose that the weak and inconsistent associations of 17q single nucleotide polymorphisms with asthma in African Americans is due to the high frequency of some 17q alleles, the breakdown of linkage disequilibrium on African-derived chromosomes, and possibly different early-life asthma endotypes in these children. Finally, the inconsistent association between asthma and gene expression levels in blood or lung cells from older children and adults suggests that genotype effects may mediate asthma risk or protection during critical developmental windows and/or in response to relevant exposures in early life. Thus studies of young children and ethnically diverse populations are required to fully understand the relationship between genotype and asthma phenotype and the gene regulatory architecture at this locus.
| S-EPMC6172038 | biostudies-literature
Project description:Sarcoidosis is a chronic granulomatous disease with a wide spectrum of symptoms. Genome-wide association studies in European populations have reported significant associations between sarcoidosis and single-nucleotide polymorphisms (SNPs) located in the intergenic region between the C10ORF67 and OTUD1 genes on chromosome 10p12, and the ANXA11 gene (chromosome 10q22). We carried out fine-mapping at 10p12 and 10q22 to assess associations of genetic variants in these regions with sarcoidosis risk in African-American women, based on 486 sarcoidosis cases and 943 age- and geography-matched controls in a nested case-control study within the Black Women's Health Study. There were no significant associations with variants of the ANXA11 gene (P=0.17). Haplotypic analyses of the C10ORF67-OTUD1 intergenic region revealed a strong inverse association of the variants rs1398024 and rs11013452 with sarcoidosis (odds ratio=0.52; P=0.01). Both SNPs are located inside an ?300?kb low recombination region of chromosome 10p12, suggesting that both SNPs are tagging the same causal variant. Our top SNP (rs11013452) is located inside a smaller linkage disequilibrium block in HapMap YRI, further narrowing the position of the causal SNP to a region of ~8?kb on chromosome 10p12. The present findings confirm the potential importance of the 10p12 locus in the etiology of sarcoidosis.
| S-EPMC3475762 | biostudies-literature
Project description:BackgroundAsthma is a chronic inflammatory disorder with a strong genetic inheritance. Although more than 100 loci were reported through the genome-wide association study of European populations, the genetic underpinning of asthma in African American individuals remains largely elusive.ObjectiveWe aimed to identify genetic loci associated with asthma in African American individuals.MethodsThree cohorts were genotyped at the Children's Hospital of Philadelphia by using the Illumina single-nucleotide polymorphism array platform. Genotype imputation was performed by using the Trans-Omics for Precision Medicine (TOPMed) reference panel, which includes whole genome sequencing data from more than 100,000 individuals. A meta-analysis of 3 Children's Hospital of Philadelphia cohorts and 10 Consortium on Asthma among African Ancestry Populations in the Americas cohorts, totaling 19,628 subjects, was conducted to identify genetic loci associated with asthma in African American individuals.ResultsOur study identified 12 loci surpassing the classical genome-wide significance threshold (5 × 10-8). Of those loci, 8 reached the stricter significance threshold (3 × 10-8). The 9p24.1 locus (rs10975467 [P = 1.63 × 10-8]) has previously been associated with asthma in European individuals. Six loci are associated with enhancer activities, 2 loci are in DNase I-hypersensitive regions, and all of them are associated with regulatory motifs. Moreover, the locus 11q13.4 (rs7480008) is an expression quantitative trait locus of XRRA1 in lung (P = 9.4 × 10-10), and the locus 13q14.3 (rs1543525) is a splicing quantitative trait locus of DHRS12 in lung (P = 1.1 × 10-13).ConclusionsOur findings provide candidate genetic loci for therapeutic target identification and prioritization for African populations.
| S-EPMC9992439 | biostudies-literature