Dataset Information

Integrative Genomics Analysis Unravels Tissue-Specific Pathways, Networks, and Key Regulators of Blood Pressure Regulation.

ABSTRACT: Blood pressure (BP) is a highly heritable trait and a major cardiovascular disease risk factor. Genome wide association studies (GWAS) have implicated a number of susceptibility loci for systolic (SBP) and diastolic (DBP) blood pressure. However, a large portion of the heritability cannot be explained by the top GWAS loci and a comprehensive understanding of the underlying molecular mechanisms is still lacking. Here, we utilized an integrative genomics approach that leveraged multiple genetic and genomic datasets including (a) GWAS for SBP and DBP from the International Consortium for Blood Pressure (ICBP), (b) expression quantitative trait loci (eQTLs) from genetics of gene expression studies of human tissues related to BP, (c) knowledge-driven biological pathways, and (d) data-driven tissue-specific regulatory gene networks. Integration of these multidimensional datasets revealed tens of pathways and gene subnetworks in vascular tissues, liver, adipose, blood, and brain functionally associated with DBP and SBP. Diverse processes such as platelet production, insulin secretion/signaling, protein catabolism, cell adhesion and junction, immune and inflammation, and cardiac/smooth muscle contraction, were shared between DBP and SBP. Furthermore, "Wnt signaling" and "mammalian target of rapamycin (mTOR) signaling" pathways were found to be unique to SBP, while "cytokine network", and "tryptophan catabolism" to DBP. Incorporation of gene regulatory networks in our analysis informed on key regulator genes that orchestrate tissue-specific subnetworks of genes whose variants together explain ~20% of BP heritability. Our results shed light on the complex mechanisms underlying BP regulation and highlight potential novel targets and pathways for hypertension and cardiovascular diseases.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC6423920 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Integrative Genomics Analysis Unravels Tissue-Specific Pathways, Networks, and Key Regulators of Blood Pressure Regulation.

Zhao Yuqi Y Blencowe Montgomery M Shi Xingyi X Shu Le L Levian Candace C Ahn In Sook IS Kim Stuart K SK Huan Tianxiao T Levy Daniel D Yang Xia X

Frontiers in cardiovascular medicine 20190312

Blood pressure (BP) is a highly heritable trait and a major cardiovascular disease risk factor. Genome wide association studies (GWAS) have implicated a number of susceptibility loci for systolic (SBP) and diastolic (DBP) blood pressure. However, a large portion of the heritability cannot be explained by the top GWAS loci and a comprehensive understanding of the underlying molecular mechanisms is still lacking. Here, we utilized an integrative genomics approach that leveraged multiple genetic an ...[more]

PMID: 30931314

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Project description:Plant primary metabolism is a highly coordinated, central, and complex network of biochemical processes regulated at both the genetic and post-translational levels. The genetic basis of this network can be explored by analyzing the metabolic composition of genetically diverse genotypes in a given plant species. Here, we report an integrative strategy combining quantitative genetic mapping and metabolite?transcript correlation networks to identify functional associations between genes and primary metabolites in Arabidopsis thaliana. Genome-wide association study (GWAS) was used to identify metabolic quantitative trait loci (mQTL). Correlation networks built using metabolite and transcript data derived from a previously published time-course stress study yielded metabolite?transcript correlations identified by covariation. Finally, results obtained in this study were compared with mQTL previously described. We applied a statistical framework to test and compare the performance of different single methods (network approach and quantitative genetics methods, representing the two orthogonal approaches combined in our strategy) with that of the combined strategy. We show that the combined strategy has improved performance manifested by increased sensitivity and accuracy. This combined strategy allowed the identification of 92 candidate associations between structural genes and primary metabolites, which not only included previously well-characterized gene?metabolite associations, but also revealed novel associations. Using loss-of-function mutants, we validated two of the novel associations with genes involved in tyrosine degradation and in ?-alanine metabolism. In conclusion, we demonstrate that applying our integrative strategy to the largely untapped resource of metabolite-transcript associations can facilitate the discovery of novel metabolite-related genes. This integrative strategy is not limited to A. thaliana, but generally applicable to other plant species.

Dataset Information

Integrative Genomics Analysis Unravels Tissue-Specific Pathways, Networks, and Key Regulators of Blood Pressure Regulation.

Publications

Integrative Genomics Analysis Unravels Tissue-Specific Pathways, Networks, and Key Regulators of Blood Pressure Regulation.

Similar Datasets

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