Chronic obstructive pulmonary disease (COPD) is a heterogeneous group of chronic lung conditions. Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) associated with COPD and the co-occurring conditions, suggesting common biological mechanisms underlying COPD and these co-occurring conditions. To identify them, we have integrated information across different biological levels (i.e., genetic variants, lung-specific 3D genome structure, gene expression and protein–protein interactions) to build lung-specific gene regulatory and protein–protein interaction networks. We have queried these networks using disease-associated SNPs for COPD, unipolar depression and coronary artery disease. COPD-associated SNPs can control genes involved in the regulation of lung or pulmonary function, asthma, brain region volumes, cortical surface area, depressed affect, neuroticism, Parkinson’s disease, white matter microstructure and smoking behaviour. We describe the regulatory connections, genes and biochemical pathways that underlay these co-occurring trait-SNP-gene associations. Collectively, our findings provide new avenues for the investigation of the underlying biology and diverse clinical presentations of COPD. In so doing, we identify a collection of genetic variants and genes that may aid COPD patient stratification and treatment.
IntroductionA novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was recently identified as the pathogen responsible for the COVID-19 outbreak. SARS-CoV-2 triggers severe pneumonia, which leads to acute respiratory distress syndrome and death in severe cases. As reported, SARS-CoV-2 is 80% genetically identical to the 2003 SARS-CoV virus. Angiotensin-converting enzyme 2 (ACE2) has been identified as the main receptor for entry of both SARS-CoV and SARS-CoV-2 into human cells. ACE2 is normally expressed in cardiovascular and lung type II alveolar epithelial cells, where it positively modulates the RAS system that regulates blood flow, pressure, and fluid homeostasis. Thus, virus-induced reduction of ACE2 gene expression is considered to make a significant contribution to severe acute respiratory failure. Chromatin remodeling plays a significant role in the regulation of ACE2 gene expression and the activity of regulatory elements within the genome.MethodsHere, we integrated data on physical chromatin interactions within the genome organization (captured by Hi-C) with tissue-specific gene expression data to identify spatial expression quantitative trait loci (eQTLs) and thus regulatory elements located within the ACE2 gene.ResultsWe identified regulatory elements within ACE2 that control the expression of PIR, CA5B, and VPS13C in the lung. The gene products of these genes are involved in inflammatory responses, de novo pyrimidine and polyamine synthesis, and the endoplasmic reticulum, respectively.ConclusionOur study, although limited by the fact that the identification of the regulatory interactions is putative until proven by targeted experiments, supports the hypothesis that viral silencing of ACE2 alters the activity of gene regulatory regions and promotes an intra-cellular environment suitable for viral replication.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by significant and complex genetic etiology. GWAS studies have identified genetic variants associated with ASD, but the functional impacts of these variants remain unknown. Here, we integrated four distinct levels of biological information (GWAS, eQTL, spatial genome organization and protein–protein interactions) to identify potential regulatory impacts of ASD-associated SNPs (p < 5 × 10–8) on biological pathways within fetal and adult cortical tissues. We found 80 and 58 SNPs that mark regulatory regions (i.e. expression quantitative trait loci or eQTLs) in the fetal and adult cortex, respectively. These eQTLs were also linked to other psychiatric disorders (e.g. schizophrenia, ADHD, bipolar disorder). Functional annotation of ASD-associated eQTLs revealed that they are involved in diverse regulatory processes. In particular, we found significant enrichment of eQTLs within regions repressed by Polycomb proteins in the fetal cortex compared to the adult cortex. Furthermore, we constructed fetal and adult cortex-specific protein–protein interaction networks and identified that ASD-associated regulatory SNPs impact on immune pathways, fatty acid metabolism, ribosome biogenesis, aminoacyl-tRNA biosynthesis and spliceosome in the fetal cortex. By contrast, in the adult cortex they largely affect immune pathways. Overall, our findings highlight potential regulatory mechanisms and pathways important for the etiology of ASD in early brain development and adulthood. This approach, in combination with clinical studies on ASD, will contribute to individualized mechanistic understanding of ASD development.
The latest meta-analysis of genome wide association studies (GWAS) identified 90 independent variants across 78 genomic regions associated with Parkinson’s disease, yet the mechanisms by which these variants influence the development of the disease remains largely elusive. To establish the functional gene regulatory networks associated with Parkinson’s disease risk variants, we utilised an approach combining spatial (chromosomal conformation capture) and functional (expression quantitative trait loci; eQTL) data. We identified 518 genes subject to regulation by 76 Parkinson’s-variants across 49 tissues, that encompass 36 peripheral and 13 CNS tissues. Notably, one third of these genes were regulated via trans- acting mechanisms (distal; risk locus-gene separated by > 1Mb, or on different chromosomes). Of particular interest is the identification of a novel trans-eQTL-gene connection between rs10847864 and SYNJ1 in the adult brain cortex, highlighting a convergence between familial studies and Parkinson’s disease GWAS loci for SYNJ1 (PARK20) for the first time. Furthermore, we identified 16 neuro-development specific eQTL-gene regulatory connections within the foetal cortex, consistent with hypotheses suggesting a neurodevelopmental involvement in the pathogenesis of Parkinson’s disease. Through utilising Louvain clustering we extracted nine significant and highly intra-connected clusters within the entire gene regulatory network. The nine clusters are enriched for specific biological processes and pathways, some of which have not previously been associated with Parkinson’s. Together, our results not only contribute to an overall understanding of the mechanisms and impact of specific combinations of Parkinson’s disease variants, but also highlight the potential impact gene regulatory networks may have when elucidating aetiological subtypes of Parkinson’s disease.
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