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Exploring the molecular basis of age-related disease comorbidities using a multi-omics graphical model.

ABSTRACT: Although association studies have unveiled numerous correlations of biochemical markers with age and age-related diseases, we still lack an understanding of their mutual dependencies. To find molecular pathways that underlie age-related diseases as well as their comorbidities, we integrated aging markers from four different high-throughput omics datasets, namely epigenomics, transcriptomics, glycomics and metabolomics, with a comprehensive set of disease phenotypes from 510 participants of the TwinsUK cohort. We used graphical random forests to assess conditional dependencies between omics markers and phenotypes while eliminating mediated associations. Applying this novel approach for multi-omics data integration yields a model consisting of seven modules that represent distinct aspects of aging. These modules are connected by hubs that potentially trigger comorbidities of age-related diseases. As an example, we identified urate as one of these key players mediating the comorbidity of renal disease with body composition and obesity. Body composition variables are in turn associated with inflammatory IgG markers, mediated by the expression of the hormone oxytocin. Thus, oxytocin potentially contributes to the development of chronic low-grade inflammation, which often accompanies obesity. Our multi-omics graphical model demonstrates the interconnectivity of age-related diseases and highlights molecular markers of the aging process that might drive disease comorbidities.

SUBMITTER: Zierer J

PROVIDER: S-EPMC5122881 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Exploring the molecular basis of age-related disease comorbidities using a multi-omics graphical model.

Zierer Jonas J Pallister Tess T Tsai Pei-Chien PC Krumsiek Jan J Bell Jordana T JT Lauc Gordan G Spector Tim D TD Menni Cristina C Kastenmüller Gabi G

Scientific reports 20161125

Although association studies have unveiled numerous correlations of biochemical markers with age and age-related diseases, we still lack an understanding of their mutual dependencies. To find molecular pathways that underlie age-related diseases as well as their comorbidities, we integrated aging markers from four different high-throughput omics datasets, namely epigenomics, transcriptomics, glycomics and metabolomics, with a comprehensive set of disease phenotypes from 510 participants of the T ...[more]

PMID: 27886242

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Project description:BackgroundSingle cell RNA sequencing provides unprecedented opportunity to simultaneously explore the transcriptomic and immune receptor diversity of T and B cells. However, there are limited tools available that simultaneously analyse large multi-omics datasets integrated with metadata such as patient and clinical information.ResultsWe developed VDJView, which permits the simultaneous or independent analysis and visualisation of gene expression, immune receptors, and clinical metadata of both T and B cells. This tool is implemented as an easy-to-use R shiny web-application, which integrates numerous gene expression and TCR analysis tools, and accepts data from plate-based sorted or high-throughput single cell platforms. We utilised VDJView to analyse several 10X scRNA-seq datasets, including a recent dataset of 150,000 CD8+ T cells with available gene expression, TCR sequences, quantification of 15 surface proteins, and 44 antigen specificities (across viruses, cancer, and self-antigens). We performed quality control, filtering of tetramer non-specific cells, clustering, random sampling and hypothesis testing to discover antigen specific gene signatures which were associated with immune cell differentiation states and clonal expansion across the pathogen specific T cells. We also analysed 563 single cells (plate-based sorted) obtained from 11 subjects, revealing clonally expanded T and B cells across primary cancer tissues and metastatic lymph-node. These immune cells clustered with distinct gene signatures according to the breast cancer molecular subtype. VDJView has been tested in lab meetings and peer-to-peer discussions, showing effective data generation and discussion without the need to consult bioinformaticians.ConclusionsVDJView enables researchers without profound bioinformatics skills to analyse immune scRNA-seq data, integrating and visualising this with clonality and metadata profiles, thus accelerating the process of hypothesis testing, data interpretation and discovery of cellular heterogeneity. VDJView is freely available at https://bitbucket.org/kirbyvisp/vdjview.

Dataset Information

Exploring the molecular basis of age-related disease comorbidities using a multi-omics graphical model.

Publications

Exploring the molecular basis of age-related disease comorbidities using a multi-omics graphical model.

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