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Cytokines mapping for tissue-specific expression, eQTLs and GWAS traits.

ABSTRACT: Dysregulation in cytokine production has been linked to the pathogenesis of various immune-mediated traits, in which genetic variability contributes to the etiopathogenesis. GWA studies have identified many genetic variants in or near cytokine genes, nonetheless, the translation of these findings into knowledge of functional determinants of complex traits remains a fundamental challenge. In this study we aimed at collection, analysis and interpretation of data on cytokines focused on their tissue-specific expression, eQTLs and GWAS traits. Using GO annotations, we generated a list of 314 cytokines and analyzed them with the GTEx resource. Cytokines were highly tissue-specific, 82.3% of cytokines had Tau expression metrics???0.8. In total, 3077 associations for 1760 unique SNPs in or near 244 cytokines were mapped in the NHGRI-EBI GWAS Catalog. According to the Experimental Factor Ontology resource, the largest numbers of disease associations were related to 'Inflammatory disease', 'Immune system disease' and 'Asthma'. The GTEx-based analysis revealed that among GWAS SNPs, 1142 SNPs had eQTL effects and influenced expression levels of 999 eGenes, among them 178 cytokines. Several types of enrichment analysis showed that it was cytokines expression variability that fundamentally contributed to the molecular origins of considered immune-mediated conditions.

SUBMITTER: Salnikova LE

PROVIDER: S-EPMC7477549 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Cytokines mapping for tissue-specific expression, eQTLs and GWAS traits.

Salnikova Lyubov E LE Khadzhieva Maryam B MB Kolobkov Dmitry S DS Gracheva Alesya S AS Kuzovlev Artem N AN Abilev Serikbay K SK

Scientific reports 20200907 1

Dysregulation in cytokine production has been linked to the pathogenesis of various immune-mediated traits, in which genetic variability contributes to the etiopathogenesis. GWA studies have identified many genetic variants in or near cytokine genes, nonetheless, the translation of these findings into knowledge of functional determinants of complex traits remains a fundamental challenge. In this study we aimed at collection, analysis and interpretation of data on cytokines focused on their tissu ...[more]

PMID: 32895400

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Project description:The collection of expression quantitative trait loci (eQTLs) is an important resource to study complex traits through understanding where and how transcriptional regulations are controlled by genetic variations in the non-coding regions of the genome. Previous studies have focused on associating eQTLs with traits to identify the roles of trait-related eQTLs and their corresponding target genes involved in trait determination. Since most genes function as a part of pathways in a systematic manner, it is crucial to explore the pathways' involvements in complex traits to test potentially novel hypotheses and to reveal underlying mechanisms of disease pathogenesis. In this study, we expanded and applied loci2path software to perform large-scale eQTLs enrichment [i.e., eQTLs' target genes (eGenes) enrichment] analysis at pathway level to identify the tissue-specific enriched pathways within trait-related genomic intervals. By utilizing 13,791,909 eQTLs cataloged in the Genotype-Tissue Expression (GTEx) V8 data for 49 tissue types, 2,893 pathway sets reported from MSigDB, and query regions derived from the Phenotype-Genotype Integrator (PheGenI) catalog, we identified intriguing biological pathways that are likely to be involved in ten traits [Alzheimer's disease (AD), body mass index, Parkinson's disease (PD), schizophrenia, amyotrophic lateral sclerosis, non-small cell lung cancer (NSCLC), stroke, blood pressure, autism spectrum disorder, and myocardial infarction]. Furthermore, we extracted the most significant pathways for AD, such as BioCarta D4-GDI pathway and WikiPathways sulfation biotransformation reaction and viral acute myocarditis pathways, to study specific genes within pathways. Our data presented new hypotheses in AD pathogenesis supported by previous studies, like the increased level of caspase-3 in the amygdala that cleaves GDP dissociation inhibitor and binds to beta-amyloid, leading to increased apoptosis and neuronal loss. Our findings also revealed potential pathogenesis mechanisms for PD, schizophrenia, NSCLC, blood pressure, autism spectrum disorder, and myocardial infarction, which were consistent with past studies. Our results indicated that loci2path's eQTLs enrichment test was valuable in unveiling novel biological mechanisms of complex traits. The discovered mechanisms of disease pathogenesis and traits require further in-depth analysis and experimental validation.

Dataset Information

Cytokines mapping for tissue-specific expression, eQTLs and GWAS traits.

Publications

Cytokines mapping for tissue-specific expression, eQTLs and GWAS traits.

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