Dataset Information

Integrated genomics analysis highlights important SNPs and genes implicated in moderate-to-severe asthma based on GWAS and eQTL datasets.

ABSTRACT: BACKGROUND:Severe asthma is a chronic disease contributing to disproportionate disease morbidity and mortality. From the year of 2007, many genome-wide association studies (GWAS) have documented a large number of asthma-associated genetic variants and related genes. Nevertheless, the molecular mechanism of these identified variants involved in asthma or severe asthma risk remains largely unknown. METHODS:In the current study, we systematically integrated 3 independent expression quantitative trait loci (eQTL) data (N?=?1977) and a large-scale GWAS summary data of moderate-to-severe asthma (N?=?30,810) by using the Sherlock Bayesian analysis to identify whether expression-related variants contribute risk to severe asthma. Furthermore, we performed various bioinformatics analyses, including pathway enrichment analysis, PPI network enrichment analysis, in silico permutation analysis, DEG analysis and co-expression analysis, to prioritize important genes associated with severe asthma. RESULTS:In the discovery stage, we identified 1129 significant genes associated with moderate-to-severe asthma by using the Sherlock Bayesian analysis. Two hundred twenty-eight genes were prominently replicated by using MAGMA gene-based analysis. These 228 replicated genes were enriched in 17 biological pathways including antigen processing and presentation (Corrected P?=?4.30?×?10-?6), type I diabetes mellitus (Corrected P?=?7.09?×?10-?5), and asthma (Corrected P?=?1.72?×?10-?3). With the use of a series of bioinformatics analyses, we highlighted 11 important genes such as GNGT2, TLR6, and TTC19 as authentic risk genes associated with moderate-to-severe/severe asthma. With respect to GNGT2, there were 3 eSNPs of rs17637472 (PeQTL?=?2.98?×?10-?8 and PGWAS?=?3.40?×?10-?8), rs11265180 (PeQTL?=?6.0?×?10-?6 and PGWAS?=?1.99?×?10-?3), and rs1867087 (PeQTL?=?1.0?×?10-?4 and PGWAS?=?1.84?×?10-?5) identified. In addition, GNGT2 is significantly expressed in severe asthma compared with mild-moderate asthma (P?=?0.045), and Gngt2 shows significantly distinct expression patterns between vehicle and various glucocorticoids (Anova P?=?1.55?×?10-?6). CONCLUSIONS:Our current study provides multiple lines of evidence to support that these 11 identified genes as important candidates implicated in the pathogenesis of severe asthma.

SUBMITTER: Dong Z

PROVIDER: S-EPMC7568423 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Integrated genomics analysis highlights important SNPs and genes implicated in moderate-to-severe asthma based on GWAS and eQTL datasets.

Dong Zhouzhou Z Ma Yunlong Y Zhou Hua H Shi Linhui L Ye Gongjie G Yang Lei L Liu Panpan P Zhou Li L

BMC pulmonary medicine 20201016 1

<h4>Background</h4>Severe asthma is a chronic disease contributing to disproportionate disease morbidity and mortality. From the year of 2007, many genome-wide association studies (GWAS) have documented a large number of asthma-associated genetic variants and related genes. Nevertheless, the molecular mechanism of these identified variants involved in asthma or severe asthma risk remains largely unknown.<h4>Methods</h4>In the current study, we systematically integrated 3 independent expression q ...[more]

PMID: 33066754

Similar Datasets

Project description:ObjectivesEpidemiological studies have confirmed that low birth weight (BW) is related to neuroticism and they may have a common genetic mechanism based on phenotypic correlation research. We conducted our study on a European population with 159,208 neuroticism and 289,142 birth weight samples. In this study, we aimed to identify new neuroticism single nucleotide polymorphisms (SNPs) and pleiotropic SNPs associated with neuroticism and BW and to provide more theoretical basis for the pathogenesis of the disease.MethodsWe estimated the pleiotropic enrichment between neuroticism and BW in two independent Genome-wide association studies (GWAS) when the statistical thresholds were Conditional False Discovery Rate (cFDR) < 0.01 and Conjunctional Conditional False Discovery Rate (ccFDR) < 0.05. We performed gene annotation and gene functional analysis on the selected significant SNPs to determine the biological role of gene function and pathogenesis. Two-sample Mendelian Randomization (TSMR) analysis was performed to explore the causal relationship between the neuroticism and BW.ResultsThe conditional quantile-quantile plots (Q-Q plot) indicated that neuroticism and BW have strong genetic pleiotropy enrichment trends. With the threshold of cFDR < 0.001, we identified 126 SNPs related to neuroticism and 172 SNPs related to BW. With the threshold of ccFDR < 0.05, we identified 62 SNPs related to both neuroticism and BW. Among these SNPs, rs8039305 and rs35755513 have eQTL (expressed quantitative trait loci) and meQTL (methylation quantitative trait loci) effects simultaneously. Through GO enrichment analysis we also found that the two pathways of positive regulation of "mesenchymal cell proliferation" and "DNA-binding transcription factor activity" were significantly enriched in neuroticism and BW. Mendelian randomization analysis results indicate that there is no obvious causal relationship between neuroticism and birth weight.ConclusionWe found 126 SNPs related to neuroticism, 172 SNPs related to BW and 62 SNPs associated with both neuroticism and BW, which provided a theoretical basis for their genetic mechanism and novel potential targets for treatment/intervention development.

Dataset Information

Integrated genomics analysis highlights important SNPs and genes implicated in moderate-to-severe asthma based on GWAS and eQTL datasets.

Publications

Integrated genomics analysis highlights important SNPs and genes implicated in moderate-to-severe asthma based on GWAS and eQTL datasets.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets