An integrated cell atlas of the lung in health and disease

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(6), P. 1563 - 1577

Published: June 1, 2023

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations individual the variability present in population. Here we integrated Human Lung Cell Atlas (HLCA), combining 49 respiratory system into single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents consensus re-annotation with matching marker genes, including annotations rare previously undescribed types. Leveraging diversity individuals HLCA, identify gene modules that are associated demographic covariates such as age, sex body mass index, well changing expression along proximal-to-distal axis bronchial tree. Mapping new data to enables rapid annotation interpretation. Using reference for study disease, shared states across multiple lung diseases, SPP1

Language: Английский

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Shared and distinct genetic risk factors for childhood-onset and adult-onset asthma: genome-wide and transcriptome-wide studies

The Lancet Respiratory Medicine, Journal Year: 2019, Volume and Issue: 7(6), P. 509 - 522

Published: April 27, 2019

Language: Английский

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Sex and gender in asthma

European Respiratory Review, Journal Year: 2021, Volume and Issue: 30(162), P. 210067 - 210067

Published: Nov. 17, 2021

Asthma is a heterogenous disease, and its prevalence severity are different in males versus females through various ages. As children, boys have an increased of asthma. adults, women Sex hormones, genetic epigenetic variations, social environmental factors, responses to asthma therapeutics important factors the sex differences observed incidence, severity. For women, fluctuations hormone levels during puberty, menstrual cycle pregnancy associated with pathogenesis. Further, gene expression modifications including SARS-CoV-2 infections, symptoms. We review role genetics epigenetics, their interactions environment clinical manifestations therapeutic response

Language: Английский

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Large-scale plasma proteomics comparisons through genetics and disease associations

Nature, Journal Year: 2023, Volume and Issue: 622(7982), P. 348 - 358

Published: Oct. 4, 2023

High-throughput proteomics platforms measuring thousands of proteins in plasma combined with genomic and phenotypic information have the power to bridge gap between genome diseases. Here we performed association studies Olink Explore 3072 data generated by UK Biobank Pharma Proteomics Project

Language: Английский

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Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank

Communications Biology, Journal Year: 2021, Volume and Issue: 4(1)

Published: June 8, 2021

Abstract To identify candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on broad asthma definition (n = 56,167 cases and 352,255 controls). We then carried out functional mapping through transcriptome-wide studies (TWAS) Mendelian randomization lung 1,038) blood 31,684) tissues. The GWAS reveals 72 asthma-associated loci from 116 independent significant variants (P < 5.0E-8). most TWAS gene 17q12-q21 is GSDMB 1.42E-54). Other include TSLP 5q22, RERE 1p36, CLEC16A 16p13, IL4R 16p12, which all replicated GTEx 515). demonstrate that the largest fold enrichment regulatory annotations among blood. map 485 eQTL-regulated associated with 50 them are by randomization. Prioritization druggable known ( , IL6 TNFSF4 ) potentially new therapeutic targets for asthma.

Language: Английский

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An integrated cell atlas of the human lung in health and disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: March 11, 2022

ABSTRACT Organ- and body-scale cell atlases have the potential to transform our understanding of human biology. To capture variability present in population, these must include diverse demographics such as age ethnicity from both healthy diseased individuals. The growth size number single-cell datasets, combined with recent advances computational techniques, for first time makes it possible generate comprehensive large-scale through integration multiple datasets. Here, we integrated Human Lung Cell Atlas (HLCA) combining 46 datasets respiratory system into a single atlas spanning over 2.2 million cells 444 individuals across health disease. HLCA contains consensus re-annotation published newly generated resolving under- or misannotation 59% original enables recovery rare types, provides marker genes each type, uncovers gene modules associated demographic covariates anatomical location within system. facilitate use reference lung research allow rapid analysis new data, provide an interactive web portal project onto HLCA. Finally, demonstrate value interpreting disease-associated changes. Thus, outlines roadmap development organ-scale Atlas.

Language: Английский

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Human germline heterozygous gain-of-functionSTAT6variants cause severe allergic disease

The Journal of Experimental Medicine, Journal Year: 2023, Volume and Issue: 220(5)

Published: March 8, 2023

STAT6 (signal transducer and activator of transcription 6) is a factor that plays central role in the pathophysiology allergic inflammation. We have identified 16 patients from 10 families spanning three continents with profound phenotype early-life onset immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All carried monoallelic rare variants functional studies established their gain-of-function (GOF) sustained phosphorylation, increased target gene expression, TH2 skewing. Precision treatment anti–IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations immunological biomarkers. This study identifies heterozygous GOF as novel disorder. anticipate our discovery multiple kindreds germline will facilitate recognition more affected individuals full definition this new primary

Language: Английский

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Decoding the genetic and epigenetic basis of asthma

Allergy, Journal Year: 2023, Volume and Issue: 78(4), P. 940 - 956

Published: Feb. 2, 2023

Abstract Asthma is a complex and heterogeneous chronic inflammatory disease of the airways. Alongside environmental factors, asthma susceptibility strongly influenced by genetics. Given its high prevalence our incomplete understanding mechanisms underlying susceptibility, frequently studied in genome‐wide association studies (GWAS), which have identified thousands genetic variants associated with development. Virtually all these reside non‐coding genomic regions, has obscured functional impact asthma‐associated their translation into disease‐relevant mechanisms. Recent advances genomics technology epigenetics now offer methods to link gene regulatory elements embedded within started unravel molecular (epi)genetics asthma. Here, we provide an integrated overview (epi)genetic asthma, focusing on efforts associations biological insight pathophysiology using state‐of‐the‐art methodology. Finally, perspective as how decoding epigenetic basis potential transform clinical management predict risk

Language: Английский

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Effect of air pollution on asthma

Annals of Allergy Asthma & Immunology, Journal Year: 2024, Volume and Issue: 132(4), P. 426 - 432

Published: Jan. 21, 2024

Language: Английский

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Multi-ancestry meta-analysis of asthma identifies novel associations and highlights the value of increased power and diversity

Cell Genomics, Journal Year: 2022, Volume and Issue: 2(12), P. 100212 - 100212

Published: Nov. 8, 2022

Asthma is a complex disease that varies widely in prevalence across populations. The extent to which genetic variation contributes these disparities unclear, as the genetics underlying asthma have been investigated primarily populations of European descent. As part Global Biobank Meta-analysis Initiative, we conducted large-scale genome-wide association study (153,763 cases and 1,647,022 controls) via meta-analysis 22 biobanks spanning multiple ancestries. We discovered 179 asthma-associated loci, 49 were not previously reported. Despite wide range among biobanks, found largely consistent effects also improved polygenic risk prediction non-European compared with previous studies. Additionally, considerable overlap between age-of-onset subtypes comorbid diseases. Our work underscores multi-factorial nature development offers insight into its shared architecture.

Language: Английский

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