Dataset Information

Multi-ancestry genome-wide association study of asthma exacerbations.

ABSTRACT:

Background

Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression.

Methods

A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10^-5 ) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico.

Results

One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (OR_{T allele} ) = 0.82, p = 9.05 × 10^-6 and replication: OR_{T allele} = 0.89, p = 5.35 × 10^-3 ) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: OR_{C allele} = 0.85, p = 3.10 × 10^-5 and replication: OR_{C allele} = 0.89, p = 1.30 × 10^-2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood.

Conclusions

This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.

SUBMITTER: Herrera-Luis E

PROVIDER: S-EPMC9671132 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Publications

Multi-ancestry genome-wide association study of asthma exacerbations.

Herrera-Luis Esther E Ortega Victor E VE Ampleford Elizabeth J EJ Sio Yang Yie YY Granell Raquel R de Roos Emmely E Terzikhan Natalie N Vergara Ernesto Elorduy EE Hernandez-Pacheco Natalia N Perez-Garcia Javier J Martin-Gonzalez Elena E Lorenzo-Diaz Fabian F Hashimoto Simone S Brinkman Paul P Jorgensen Andrea L AL Yan Qi Q Forno Erick E Vijverberg Susanne J SJ Lethem Ryan R Espuela-Ortiz Antonio A Gorenjak Mario M Eng Celeste C González-Pérez Ruperto R Hernández-Pérez José M JM Poza-Guedes Paloma P Sardón Olaia O Corcuera Paula P Hawkins Greg A GA Marsico Annalisa A Bahmer Thomas T Rabe Klaus F KF Hansen Gesine G Kopp Matthias Volkmar MV Rios Raimon R Cruz Maria Jesus MJ González-Barcala Francisco-Javier FJ Olaguibel José María JM Plaza Vicente V Quirce Santiago S Canino Glorisa G Cloutier Michelle M Del Pozo Victoria V Rodriguez-Santana Jose R JR Korta-Murua Javier J Villar Jesús J Potočnik Uroš U Figueiredo Camila C Kabesch Michael M Mukhopadhyay Somnath S Pirmohamed Munir M Hawcutt Daniel B DB Melén Erik E Palmer Colin N CN Turner Steve S Maitland-van der Zee Anke H AH von Mutius Erika E Celedón Juan C JC Brusselle Guy G Chew Fook Tim FT Bleecker Eugene E Meyers Deborah D Burchard Esteban G EG Pino-Yanes Maria M

Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology 20220601 6

<h4>Background</h4>Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across div ...[more]

PMID: 35754128

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Project description:BackgroundFew genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma.MethodsIn this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10-6 in stage 1. We set genome-wide significance at p less than 5 × 10-8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls.FindingsWe included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10-10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06-1·12; p=2·32 × 10-8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08-1·16; p=3·06 × 10-9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10-5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022).InterpretationWe found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population.FundingAsthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust.

Project description:Background & aimsSpontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance, but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry.MethodsWe performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina (San Diego, CA) arrays and statistically imputed to the 1000 Genomes Project. For each ancestry group, the association of single-nucleotide polymorphisms with HCV clearance was tested by log-additive analysis, and then a meta-analysis was performed.ResultsIn the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4-IFNL3 (19q13.2) (P = 5.99 × 10-50) and the MHC locus 6p21.32 (P = 1.15 × 10-21). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P = 1.80 × 10-07). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared with individuals carrying none or 1 of the clearance-associated variants.ConclusionsIn a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4-IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection.

Dataset Information

Multi-ancestry genome-wide association study of asthma exacerbations.

Background

Methods

Results

Conclusions

Publications

Multi-ancestry genome-wide association study of asthma exacerbations.

Similar Datasets

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