Tissue-specific and tissue-agnostic effects of genome sequence variation modulating blood pressure

Lee, Dongwon; Han, Seong Kyu; Yaacov, Or; Berk-Rauch, Hanna; Mathiyalagan, Prabhu; Ganesh, Santhi K.; Chakravarti, Aravinda

doi:10.1016/j.celrep.2023.113351

Cited by 3 publications

(17 citation statements)

References 60 publications

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“…Clearly, our gene expression analysis is only significant in the artery and not in the three other tissues. This is consistent with previous work on the role of MTHFR in blood pressure regulation 27 and with our previous work demonstrating significant CRE associations of MTHFR with BP in arteries 7 and in arteries and heart 8 . These results provide the evidence to support causality of both MTHFR and NPPB , but with distinct biological functions in distinct tissues.…”

Section: Resultssupporting

confidence: 93%

“…Our previous work 8 demonstrated that regulatory variants specific to the artery have the largest (11.8%) contribution to BP heritability, followed by those from the heart (7.7%) and adrenal (5.3%); surprisingly, the kidney-specific CRE variants had the lowest contribution (2.5%), consistent with prior GWAS data. 7,9,10…”

Section: Introductionsupporting

confidence: 85%

“…Human samples of the same tissue vary in the peaks they capture as a result of technical and biological factors, as the tissues were procured from different donors. 8 We, therefore, created one comprehensive map for each tissue, using the best-performing CREs as determined by our quality assessment using gkmQC. 16 The final numbers of CREs that passed our quality control parameters, as described in the Methods section, and based on our previous work, 8 are 141,510, 133,231, 132,970, 104,812 in the adrenal, kidney, heart, and tibial artery, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…8 We, therefore, created one comprehensive map for each tissue, using the best-performing CREs as determined by our quality assessment using gkmQC. 16 The final numbers of CREs that passed our quality control parameters, as described in the Methods section, and based on our previous work, 8 are 141,510, 133,231, 132,970, 104,812 in the adrenal, kidney, heart, and tibial artery, respectively. These CREs in these tissues cover 12.2%, 11.4%, 13.6% and 11.1% of the genome, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…These numbers are consistent with previous works. 7,8 The result is a tissue-restricted map of common variants in CREs and their associated impact on chromatin accessibility in that tissue as measured by deltaSVM scores.…”

Section: Resultsmentioning

confidence: 99%

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Identification of the molecular components of enhancer-mediated gene expression variation in multiple tissues regulating blood pressure

Yaacov,

Mathiyalagan,

Berk-Rauch

et al. 2023

Preprint

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Inter-individual variation in blood pressure (BP) arises in part from sequence variants within numerous enhancers modulating expression of an unknown number of causal genes. We propose that these genes are active in tissues relevant to BP physiology and can be identified from tissue epigenomic data and genotypes of BP-phenotyped individuals. We used the ENCODE project’s H3K27ac and ATAC-seq data from the heart, adrenal gland, kidney, and artery to comprehensively identify all cis regulatory elements (CREs) in these tissues to estimate the impact of all common human single nucleotide variants (SNVs) in CREs on gene expression, using machine learning methods. To identify specific genes, we integrated these results through a gene-wise association test against BP. We conducted analyses in two separate large-scale cohorts: 77,822 individuals from the Genetic Epidemiology Research on Adult Health and Aging (GERA) of Kaiser Permanente North California and 315,270 individuals from the UK Biobank (UKB).We identified 309, 259, 331 and 367 genes (FDR<0.05) for diastolic BP (DBP), and 191, 184, 204, and 204 genes for systolic BP (SBP), in the artery, kidney, heart, and adrenal gland, respectively, in GERA; 50-70% of these genes were replicated in the UKB and is significantly higher than the 12-15% expected by chance (P <10-4). These results enabled the prediction of tissue expression of these 988-2,875 putative BP-genes in individual participants of both cohorts to construct an expression polygenic score (exPGS). This score explained ∼27% of the reported SNV heritability (h2, 21%), substantially higher than that expected from prior studies. Additionally, we utilized these methods to provide dual-modality supporting evidence, CRE and expression-based, for the causality of genes previously detected by GWAS.

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Section: Resultssupporting

confidence: 93%

Section: Introductionsupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Identification of the molecular components of enhancer-mediated gene expression variation in multiple tissues regulating blood pressure

Yaacov,

Mathiyalagan,

Berk-Rauch

et al. 2023

Preprint

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Sex-specific genetic architecture of blood pressure

Yang,

Xu,

Gupte

et al. 2024

Nat Med

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Identification of the Molecular Components of Enhancer-Mediated Gene Expression Variation in Multiple Tissues Regulating Blood Pressure

Yaacov,

Mathiyalagan,

Berk-Rauch

et al. 2024

Hypertension

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BACKGROUND: Inter-individual variation in blood pressure (BP) arises in part from sequence variants within enhancers modulating the expression of causal genes. We propose that these genes, active in tissues relevant to BP physiology, can be identified from tissue-level epigenomic data and genotypes of BP-phenotyped individuals. METHODS: We used chromatin accessibility data from the heart, adrenal, kidney, and artery to identify cis-regulatory elements (CREs) in these tissues and estimate the impact of common human single-nucleotide variants within these CREs on gene expression, using machine learning methods. To identify causal genes, we performed a gene-wise association test. We conducted analyses in 2 separate large-scale cohorts: 77 822 individuals from the Genetic Epidemiology Research on Adult Health and Aging and 315 270 individuals from the UK Biobank. RESULTS: We identified 309, 259, 331, and 367 genes (false discovery rate <0.05) for diastolic BP and 191, 184, 204, and 204 genes for systolic BP in the artery, kidney, heart, and adrenal, respectively, in Genetic Epidemiology Research on Adult Health and Aging; 50% to 70% of these genes were replicated in the UK Biobank, significantly higher than the 12% to 15% expected by chance ( P <0.0001). These results enabled tissue expression prediction of these 988 to 2875 putative BP genes in individuals of both cohorts to construct an expression polygenic score. This score explained ≈27% of the reported single-nucleotide variant heritability, substantially higher than expected from prior studies. CONCLUSIONS: Our work demonstrates the power of tissue-restricted comprehensive CRE analysis, followed by CRE-based expression prediction, for understanding BP regulation in relevant tissues and provides dual-modality supporting evidence, CRE and expression, for the causality genes.

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Tissue-specific and tissue-agnostic effects of genome sequence variation modulating blood pressure

Cited by 3 publications

References 60 publications

Identification of the molecular components of enhancer-mediated gene expression variation in multiple tissues regulating blood pressure

Identification of the molecular components of enhancer-mediated gene expression variation in multiple tissues regulating blood pressure

Sex-specific genetic architecture of blood pressure

Identification of the Molecular Components of Enhancer-Mediated Gene Expression Variation in Multiple Tissues Regulating Blood Pressure

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