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Background: More than 200 asthma-associated genetic variants have been identified in genome-wide association studies (GWASs). Expression quantitative trait loci (eQTL) data resources can help identify causal genes of the GWAS signals, but it can be difficult to find an eQTL that reflects the disease state because most eQTL data are obtained from normal healthy subjects. Methods: We performed a blood eQTL analysis using transcriptomic and genotypic data from 433 Korean asthma patients. To identify asthma-related genes, we carried out colocalization, Summary-based Mendelian Randomization (SMR) analysis, and Transcriptome-Wide Association Study (TWAS) using the results of asthma GWASs and eQTL data. In addition, we compared the results of disease eQTL data and asthma-related genes with two normal blood eQTL data from Genotype-Tissue Expression (GTEx) project and a Japanese study. Results: We identified 340,274 cis-eQTL and 2,875 eGenes from asthmatic eQTL analysis. We compared the disease eQTL results with GTEx and a Japanese study and found that 64.1% of the 2,875 eGenes overlapped with the GTEx eGenes and 39.0% with the Japanese eGenes. Following the integrated analysis of the asthmatic eQTL data with asthma GWASs, using colocalization and SMR methods, we identified 15 asthma-related genes specific to the Korean asthmatic eQTL data. Conclusions: We provided Korean asthmatic cis-eQTL data and identified asthma-related genes by integrating them with GWAS data. In addition, we suggested these asthma-related genes as therapeutic targets for asthma. We envisage that our findings will contribute to understanding the etiological mechanisms of asthma and provide novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: The extent of differences between genetic risks associated with various asthma subtypes is still unknown. To better understand the heterogeneity of asthma, we employed an unsupervised method to identify genetic variants specifically associated with asthma subtypes. Our goal was to gain insight into the genetic basis of asthma. Methods: In this study, we utilized the UK Biobank dataset to select asthma patients (All asthma, n = 50,517) and controls (n = 283,410). We excluded 14,431 individuals who had no information on predicted values of forced expiratory volume in one second percent (FEV1%) and onset age, resulting in a final total of 36,086 asthma cases. We conducted k‐means clustering based on asthma onset age and predicted FEV1% using these samples (n = 36,086). Cluster‐specific genome‐wide association studies were then performed, and heritability was estimated via linkage disequilibrium score regression. To further investigate the pathophysiology, we conducted eQTL analysis with GTEx and gene‐set enrichment analysis with FUMA. Results: Clustering resulted in four distinct clusters: early onset asthmanormalLF (early onset with normal lung function, n = 8172), early onset asthmareducedLF (early onset with reduced lung function, n = 8925), late‐onset asthmanormalLF (late‐onset with normal lung function, n = 12,481), and late‐onset asthmareducedLF (late‐onset with reduced lung function, n = 6508). Our GWASs in four clusters and in All asthma sample identified 5 novel loci, 14 novel signals, and 51 cluster‐specific signals. Among clusters, early onset asthmanormalLF and late‐onset asthmareducedLF were the least correlated (rg = 0.37). Early onset asthmareducedLF showed the highest heritability explained by common variants (h2 = 0.212) and was associated with the largest number of variants (71 single nucleotide polymorphisms). Further, the pathway analysis conducted through eQTL and gene‐set enrichment analysis showed that the worsening of symptoms in early onset asthma correlated with lymphocyte activation, pathogen recognition, cytokine receptor activation, and lymphocyte differentiation. Conclusions: Our findings suggest that early onset asthmareducedLF was the most genetically predisposed cluster, and that asthma clusters with reduced lung function were genetically distinct from clusters with normal lung function. Our study revealed the genetic variation between clusters that were segmented based on onset age and lung function, providing an important clue for the genetic mechanism of asthma heterogeneity. [ABSTRACT FROM AUTHOR]

Asthma is a complex disease that is reportedly associated with insomnia. However, the causal directionality of this association is still unclear. We used asthma and insomnia-associated single nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) summary statistics to test the causal directionality between insomnia and asthma via Mendelian randomization (MR) analysis. We also performed a cross-trait meta-analysis using UK Biobank GWAS summary statistics and a gene–environment interaction study using data from UK Biobank. The interaction of genetic risk score for asthma (GRSasthma) with insomnia on asthma was tested by logistic regression. Insomnia was a risk factor for the incidence of asthma, as revealed by three different methods of MR analysis. However, asthma did not act as a risk factor for insomnia. The cross-trait meta-analysis identified 28 genetic loci shared between asthma and insomnia. In the gene–environment interaction study, GRSasthma interacted with insomnia to significantly affect the risk of asthma. The results of this study highlight the importance of insomnia as a risk factor of asthma, and warrant further analysis of the mechanism through which insomnia affects the risk of asthma. [ABSTRACT FROM AUTHOR]

Although asthma is one of the most common chronic diseases throughout all age groups, its etiology remains unknown, primarily due to its heterogeneous characteristics. We examined the causal effects of various environmental factors on asthma using Mendelian randomization and determined whether the susceptibility to asthma due to the causal effect of a risk factor differs between asthma subtypes, based on age of onset, severity of asthma, and sex. We performed Mendelian randomization analyses (inverse variance weighted, weighted median, and generalized summary-data-based Mendelian randomization) using UK Biobank data to estimate the causal effects of 69 environmental factors on asthma. Additional sensitivity analyses (MR-Egger regression, Cochran's Q test, clumping, and reverse Mendelian randomization) were performed to ensure minimal or no pleiotropy. For confirmation, two-sample setting analyses were replicated using BMI SNPs that had been reported by a meta-genome-wide association study in Japanese and European (GIANT) populations and a genome-wide association study in control individuals from the UK Biobank. We found that BMI causally affects the development of asthma and that the adult-onset moderate-to-severe asthma subtype is the most susceptible to causal inference by BMI. Further, it is likely that the female subtype is more susceptible to BMI than males among adult asthma cases. Our findings provide evidence that obesity is a considerable risk factor in asthma patients, particularly in adult-onset moderate-to-severe asthma cases, and that weight loss is beneficial for reducing the burden of asthma. [ABSTRACT FROM AUTHOR]