Integrative genomic analysis in African American children with asthma finds three novel loci associated with lung function

Goddard, Pagé C.; Keys, Kevin L.; Mak, Angel C. Y.; Lee, Eunice; Liu, Amy K.; Samedy‐Bates, Lesly‐Anne; Risse-Adams, Oona; Contreras, María G.; Elhawary, Jennifer R.; Hu, Donglei; Huntsman, Scott; Oh, Sam S.; Salazar, Sandra; Eng, Celeste; Himes, Blanca E.; White, Marquitta J.; Burchard, Esteban G.

doi:10.1002/gepi.22365

Cited by 5 publications

(3 citation statements)

References 106 publications

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“…The linear mixed models also included a genetic relatedness matrix as a random effect to account for residual population structure. Because children with asthma have lower lung function overall (Table 1) and their lung function may be more affected by environmental exposures [110][111][112], we adjusted for asthma status in the GWAS, as in previous GWAS [113][114][115][116]. The likelihood of discovering lung function variants with consistent effects in asthmatics and non-asthmatics was thereby increased, although genetic determinants of lung function may differ by asthma status [117].…”

Section: Plos Geneticsmentioning

confidence: 99%

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings

et al. 2023

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Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; βz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; β = 0.12, 95% CI = 0.06–0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.

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Section: Plos Geneticsmentioning

confidence: 99%

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings

et al. 2023

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“…The linear mixed models also included a genetic relatedness matrix as a random effect to account for residual population structure. Because children with asthma have lower lung function overall (Table 1) and their lung function is more affected by certain environmental exposures [107][108][109] , we adjusted for asthma status in the GWAS, as others have done previously [110][111][112][113] . The likelihood of discovering lung function variants with consistent effects in asthmatics and non-asthmatics was thereby increased, although genetic determinants of lung function may differ by asthma status 114 .…”

Section: Mendelian Randomization and Mediation Analyses Indicated Tha...mentioning

confidence: 99%

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings

Dapas

Thompson

Wentworth-Sheilds

et al. 2022

Preprint

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Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n=1035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p=2.4x10-9; βz= -0.31, 95% CI= -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p=0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p=1.26x10-5; β=0.12, 95% CI=0.06- 017). These combined results highlight a potential novel mechanism for reduced lung function in urban youth through increased airway epithelial apoptosis resulting from both genetics and smoking exposure.

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“…Given the disparities in asthma prevalence and outcomes, multiple studies have leveraged locus-specific genetic ancestry to identify genetic variants associated with asthma-related outcomes 12–15. However, no admixture mapping of severe asthma exacerbations has been performed to date.…”

Section: Introductionmentioning

confidence: 99%

Admixture mapping of severe asthma exacerbations in Hispanic/Latino children and youth

Herrera‐Luis

Mak

Pérez-García

et al. 2022

Thorax

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BackgroundIn the USA, genetically admixed populations have the highest asthma prevalence and severe asthma exacerbations rates. This could be explained not only by environmental factors but also by genetic variants that exert ethnic-specific effects. However, no admixture mapping has been performed for severe asthma exacerbations.ObjectiveWe sought to identify genetic variants associated with severe asthma exacerbations in Hispanic/Latino subgroups by means of admixture mapping analyses and fine mapping, and to assess their transferability to other populations and potential functional roles.MethodsWe performed an admixture mapping in 1124 Puerto Rican and 625 Mexican American children with asthma. Fine-mapping of the significant peaks was performed via allelic testing of common and rare variants. We performed replication across Hispanic/Latino subgroups, and the transferability to non-Hispanic/Latino populations was assessed in 1001 African Americans, 1250 Singaporeans and 941 Europeans with asthma. The effects of the variants on gene expression and DNA methylation from whole blood were also evaluated in participants with asthma and in silico with data obtained through public databases.ResultsGenomewide significant associations of Indigenous American ancestry with severe asthma exacerbations were found at 5q32 in Mexican Americans as well as at 13q13-q13.2 and 3p13 in Puerto Ricans. The single nucleotide polymorphism (SNP) rs1144986 (C5orf46) showed consistent effects for severe asthma exacerbations across Hispanic/Latino subgroups, but it was not validated in non-Hispanics/Latinos. This SNP was associated with DPYSL3 DNA methylation and SCGB3A2 gene expression levels.ConclusionsAdmixture mapping study of asthma exacerbations revealed a novel locus that exhibited Hispanic/Latino-specific effects and regulated DPYSL3 and SCGB3A2.

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Integrative genomic analysis in African American children with asthma finds three novel loci associated with lung function

Cited by 5 publications

References 106 publications

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings

Admixture mapping of severe asthma exacerbations in Hispanic/Latino children and youth

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