Integration of functional genomics and statistical fine-mapping systematically characterizes adult-onset and childhood-onset asthma genetic associations DOI Creative Commons
Xiaoyuan Zhong,

Robert D. Mitchell,

Christine Billstrand

et al.

Genome Medicine, Journal Year: 2025, Volume and Issue: 17(1)

Published: April 9, 2025

Abstract Background Genome-wide association studies (GWAS) have identified hundreds of loci underlying adult-onset asthma (AOA) and childhood-onset (COA). However, the causal variants, regulatory elements, effector genes at these are largely unknown. Methods We performed heritability enrichment analysis to determine relevant cell types for AOA COA, respectively. Next, we fine-mapped putative variants COA loci. To improve resolution fine-mapping, integrated ATAC-seq data in blood lung annotate candidate cis -regulatory elements (CREs). then computationally prioritized CREs risk, experimentally assessed their enhancer activity by massively parallel reporter assay (MPRA) bronchial epithelial cells (BECs) further validated a subset luciferase assays. Combining chromatin interaction expression quantitative trait loci, nominated targeted COA. Results Heritability suggested shared role immune development both while highlighting distinct contribution structural Functional fine-mapping uncovered 21 67 credible sets respectively, with only 16% between two. Notably, one-third contained multiple sets. Our CRE prioritization strategy 62 169 Over 60% showed open lineages, suggesting potential pleiotropic effects different types. Furthermore, were enriched enhancers MPRA BECs. The included many involved inflammatory responses. genes, including TNFSF4 , drug target undergoing clinical trials, supported two independent GWAS signals, indicating widespread allelic heterogeneity. Four out six selected demonstrated allele-specific properties assays Conclusions present comprehensive characterization genetics. results genetic basis highlighted complexity marked extensive pleiotropy

Language: Английский

Integration of functional genomics and statistical fine-mapping systematically characterizes adult-onset and childhood-onset asthma genetic associations DOI Creative Commons
Xiaoyuan Zhong,

Robert D. Mitchell,

Christine Billstrand

et al.

Genome Medicine, Journal Year: 2025, Volume and Issue: 17(1)

Published: April 9, 2025

Abstract Background Genome-wide association studies (GWAS) have identified hundreds of loci underlying adult-onset asthma (AOA) and childhood-onset (COA). However, the causal variants, regulatory elements, effector genes at these are largely unknown. Methods We performed heritability enrichment analysis to determine relevant cell types for AOA COA, respectively. Next, we fine-mapped putative variants COA loci. To improve resolution fine-mapping, integrated ATAC-seq data in blood lung annotate candidate cis -regulatory elements (CREs). then computationally prioritized CREs risk, experimentally assessed their enhancer activity by massively parallel reporter assay (MPRA) bronchial epithelial cells (BECs) further validated a subset luciferase assays. Combining chromatin interaction expression quantitative trait loci, nominated targeted COA. Results Heritability suggested shared role immune development both while highlighting distinct contribution structural Functional fine-mapping uncovered 21 67 credible sets respectively, with only 16% between two. Notably, one-third contained multiple sets. Our CRE prioritization strategy 62 169 Over 60% showed open lineages, suggesting potential pleiotropic effects different types. Furthermore, were enriched enhancers MPRA BECs. The included many involved inflammatory responses. genes, including TNFSF4 , drug target undergoing clinical trials, supported two independent GWAS signals, indicating widespread allelic heterogeneity. Four out six selected demonstrated allele-specific properties assays Conclusions present comprehensive characterization genetics. results genetic basis highlighted complexity marked extensive pleiotropy

Language: Английский

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