Integrative Genomics Analysis Unravels Tissue-Specific Pathways, Networks, and Key Regulators of Blood Pressure Regulation
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 explain...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-03-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fcvm.2019.00021/full |
| _version_ | 1819019039585861632 |
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| author | Yuqi Zhao Montgomery Blencowe Xingyi Shi Le Shu Candace Levian In Sook Ahn Stuart K. Kim Tianxiao Huan Tianxiao Huan Daniel Levy Daniel Levy Xia Yang |
| author_facet | Yuqi Zhao Montgomery Blencowe Xingyi Shi Le Shu Candace Levian In Sook Ahn Stuart K. Kim Tianxiao Huan Tianxiao Huan Daniel Levy Daniel Levy Xia Yang |
| author_sort | Yuqi Zhao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T03:28:59Z |
| format | Article |
| id | doaj.art-1b0b3da3cb954008852b7fbe6d7df39b |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-12-21T03:28:59Z |
| publishDate | 2019-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-1b0b3da3cb954008852b7fbe6d7df39b2022-12-21T19:17:31ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2019-03-01610.3389/fcvm.2019.00021435611Integrative Genomics Analysis Unravels Tissue-Specific Pathways, Networks, and Key Regulators of Blood Pressure RegulationYuqi Zhao0Montgomery Blencowe1Xingyi Shi2Le Shu3Candace Levian4In Sook Ahn5Stuart K. Kim6Tianxiao Huan7Tianxiao Huan8Daniel Levy9Daniel Levy10Xia Yang11Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, United StatesDepartment of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, United StatesDepartment of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, United StatesDepartment of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, United StatesDepartment of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, United StatesDepartment of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, United StatesDepartment of Genetics, Department of Developmental Biology, Stanford University Medical Center, Stanford, CA, United StatesThe National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, United StatesThe Population Sciences Branch and the Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, United StatesThe National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, United StatesThe Population Sciences Branch and the Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, United StatesDepartment of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, United StatesBlood 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.https://www.frontiersin.org/article/10.3389/fcvm.2019.00021/fullblood pressuregenome wide association studiesintegrative genomicsregulatory networkskey drivers |
| spellingShingle | Yuqi Zhao Montgomery Blencowe Xingyi Shi Le Shu Candace Levian In Sook Ahn Stuart K. Kim Tianxiao Huan Tianxiao Huan Daniel Levy Daniel Levy Xia Yang Integrative Genomics Analysis Unravels Tissue-Specific Pathways, Networks, and Key Regulators of Blood Pressure Regulation Frontiers in Cardiovascular Medicine blood pressure genome wide association studies integrative genomics regulatory networks key drivers |
| title | Integrative Genomics Analysis Unravels Tissue-Specific Pathways, Networks, and Key Regulators of Blood Pressure Regulation |
| title_full | Integrative Genomics Analysis Unravels Tissue-Specific Pathways, Networks, and Key Regulators of Blood Pressure Regulation |
| title_fullStr | Integrative Genomics Analysis Unravels Tissue-Specific Pathways, Networks, and Key Regulators of Blood Pressure Regulation |
| title_full_unstemmed | Integrative Genomics Analysis Unravels Tissue-Specific Pathways, Networks, and Key Regulators of Blood Pressure Regulation |
| title_short | Integrative Genomics Analysis Unravels Tissue-Specific Pathways, Networks, and Key Regulators of Blood Pressure Regulation |
| title_sort | integrative genomics analysis unravels tissue specific pathways networks and key regulators of blood pressure regulation |
| topic | blood pressure genome wide association studies integrative genomics regulatory networks key drivers |
| url | https://www.frontiersin.org/article/10.3389/fcvm.2019.00021/full |
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