Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets

Human Kidney Tissue Resource Study Group; Xiaoguang Xu; Chachrit Khunsriraksakul; James M Eales; Sebastien Rubin; David Scannali; Sushant Saluja; David Talavera; Havell Markus; Lida Wang; Maciej Drzal; Akhlaq Maan; Abigail C Lay; Priscilla R Prestes; Jeniece Regan; Avantika R Diwadkar; Matthew Denniff; Grzegorz Rempega; Jakub Ryszawy; Robert Król; John P Dormer; Monika Szulinska; Marta Walczak; Andrzej Antczak; Pamela R Matías-García; Melanie Waldenberger; Adrian S Woolf; Bernard Keavney; Ewa Zukowska-Szczechowska; Wojciech Wystrychowski; Joanna Zywiec; Pawel Bogdanski; A H Jan Danser; Nilesh J Samani; Tomasz J Guzik; Andrew P Morris; Dajiang J Liu; Fadi J Charchar; Maciej Tomaszewski

doi:10.1038/s41467-024-46132-y

Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets

Human Kidney Tissue Resource Study Group, Xiaoguang Xu, Chachrit Khunsriraksakul, James M Eales, Sebastien Rubin, David Scannali, Sushant Saluja, David Talavera, Havell Markus, Lida Wang, Maciej Drzal, Akhlaq Maan, Abigail C Lay, Priscilla R Prestes, Jeniece Regan, Avantika R Diwadkar, Matthew Denniff, Grzegorz Rempega, Jakub Ryszawy, Robert KrólJohn P Dormer, Monika Szulinska, Marta Walczak, Andrzej Antczak, Pamela R Matías-García, Melanie Waldenberger, Adrian S Woolf, Bernard Keavney, Ewa Zukowska-Szczechowska, Wojciech Wystrychowski, Joanna Zywiec, Pawel Bogdanski, A H Jan Danser, Nilesh J Samani, Tomasz J Guzik, Andrew P Morris, Dajiang J Liu, Fadi J Charchar, Maciej Tomaszewski

Research output: Contribution to journal › Article › peer-review

Abstract

Genetic mechanisms of blood pressure (BP) regulation remain poorly defined. Using kidney-specific epigenomic annotations and 3D genome information we generated and validated gene expression prediction models for the purpose of transcriptome-wide association studies in 700 human kidneys. We identified 889 kidney genes associated with BP of which 399 were prioritised as contributors to BP regulation. Imputation of kidney proteome and microRNAome uncovered 97 renal proteins and 11 miRNAs associated with BP. Integration with plasma proteomics and metabolomics illuminated circulating levels of myo-inositol, 4-guanidinobutanoate and angiotensinogen as downstream effectors of several kidney BP genes (SLC5A11, AGMAT, AGT, respectively). We showed that genetically determined reduction in renal expression may mimic the effects of rare loss-of-function variants on kidney mRNA/protein and lead to an increase in BP (e.g., ENPEP). We demonstrated a strong correlation (r = 0.81) in expression of protein-coding genes between cells harvested from urine and the kidney highlighting a diagnostic potential of urinary cell transcriptomics. We uncovered adenylyl cyclase activators as a repurposing opportunity for hypertension and illustrated examples of BP-elevating effects of anticancer drugs (e.g. tubulin polymerisation inhibitors). Collectively, our studies provide new biological insights into genetic regulation of BP with potential to drive clinical translation in hypertension.

Original language	English
Article number	2359
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-46132-y
Publication status	Published - 19 Mar 2024

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10.1038/s41467-024-46132-yLicence: CC BY

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Human Kidney Tissue Resource Study Group, Xu, X., Khunsriraksakul, C., Eales, J. M., Rubin, S., Scannali, D., Saluja, S., Talavera, D., Markus, H., Wang, L., Drzal, M., Maan, A., Lay, A. C., Prestes, P. R., Regan, J., Diwadkar, A. R., Denniff, M., Rempega, G., Ryszawy, J., ... Tomaszewski, M. (2024). Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets. Nature Communications, 15(1), Article 2359. https://doi.org/10.1038/s41467-024-46132-y

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title = "Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets",

abstract = "Genetic mechanisms of blood pressure (BP) regulation remain poorly defined. Using kidney-specific epigenomic annotations and 3D genome information we generated and validated gene expression prediction models for the purpose of transcriptome-wide association studies in 700 human kidneys. We identified 889 kidney genes associated with BP of which 399 were prioritised as contributors to BP regulation. Imputation of kidney proteome and microRNAome uncovered 97 renal proteins and 11 miRNAs associated with BP. Integration with plasma proteomics and metabolomics illuminated circulating levels of myo-inositol, 4-guanidinobutanoate and angiotensinogen as downstream effectors of several kidney BP genes (SLC5A11, AGMAT, AGT, respectively). We showed that genetically determined reduction in renal expression may mimic the effects of rare loss-of-function variants on kidney mRNA/protein and lead to an increase in BP (e.g., ENPEP). We demonstrated a strong correlation (r = 0.81) in expression of protein-coding genes between cells harvested from urine and the kidney highlighting a diagnostic potential of urinary cell transcriptomics. We uncovered adenylyl cyclase activators as a repurposing opportunity for hypertension and illustrated examples of BP-elevating effects of anticancer drugs (e.g. tubulin polymerisation inhibitors). Collectively, our studies provide new biological insights into genetic regulation of BP with potential to drive clinical translation in hypertension.",

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Human Kidney Tissue Resource Study Group, Xu, X, Khunsriraksakul, C, Eales, JM, Rubin, S, Scannali, D, Saluja, S, Talavera, D, Markus, H, Wang, L, Drzal, M, Maan, A, Lay, AC, Prestes, PR, Regan, J, Diwadkar, AR, Denniff, M, Rempega, G, Ryszawy, J, Król, R, Dormer, JP, Szulinska, M, Walczak, M, Antczak, A, Matías-García, PR, Waldenberger, M, Woolf, AS , Keavney, B, Zukowska-Szczechowska, E, Wystrychowski, W, Zywiec, J, Bogdanski, P, Danser, AHJ, Samani, NJ, Guzik, TJ, Morris, AP, Liu, DJ, Charchar, FJ & Tomaszewski, M 2024, 'Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets', Nature Communications, vol. 15, no. 1, 2359. https://doi.org/10.1038/s41467-024-46132-y

TY - JOUR

T1 - Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets

AU - Human Kidney Tissue Resource Study Group

AU - Xu, Xiaoguang

AU - Khunsriraksakul, Chachrit

AU - Eales, James M

AU - Rubin, Sebastien

AU - Scannali, David

AU - Saluja, Sushant

AU - Talavera, David

AU - Markus, Havell

AU - Wang, Lida

AU - Drzal, Maciej

AU - Maan, Akhlaq

AU - Lay, Abigail C

AU - Prestes, Priscilla R

AU - Regan, Jeniece

AU - Diwadkar, Avantika R

AU - Denniff, Matthew

AU - Rempega, Grzegorz

AU - Ryszawy, Jakub

AU - Król, Robert

AU - Dormer, John P

AU - Szulinska, Monika

AU - Walczak, Marta

AU - Antczak, Andrzej

AU - Matías-García, Pamela R

AU - Waldenberger, Melanie

AU - Woolf, Adrian S

AU - Keavney, Bernard

AU - Zukowska-Szczechowska, Ewa

AU - Wystrychowski, Wojciech

AU - Zywiec, Joanna

AU - Bogdanski, Pawel

AU - Danser, A H Jan

AU - Samani, Nilesh J

AU - Guzik, Tomasz J

AU - Morris, Andrew P

AU - Liu, Dajiang J

AU - Charchar, Fadi J

AU - Tomaszewski, Maciej

PY - 2024/3/19

Y1 - 2024/3/19

N2 - Genetic mechanisms of blood pressure (BP) regulation remain poorly defined. Using kidney-specific epigenomic annotations and 3D genome information we generated and validated gene expression prediction models for the purpose of transcriptome-wide association studies in 700 human kidneys. We identified 889 kidney genes associated with BP of which 399 were prioritised as contributors to BP regulation. Imputation of kidney proteome and microRNAome uncovered 97 renal proteins and 11 miRNAs associated with BP. Integration with plasma proteomics and metabolomics illuminated circulating levels of myo-inositol, 4-guanidinobutanoate and angiotensinogen as downstream effectors of several kidney BP genes (SLC5A11, AGMAT, AGT, respectively). We showed that genetically determined reduction in renal expression may mimic the effects of rare loss-of-function variants on kidney mRNA/protein and lead to an increase in BP (e.g., ENPEP). We demonstrated a strong correlation (r = 0.81) in expression of protein-coding genes between cells harvested from urine and the kidney highlighting a diagnostic potential of urinary cell transcriptomics. We uncovered adenylyl cyclase activators as a repurposing opportunity for hypertension and illustrated examples of BP-elevating effects of anticancer drugs (e.g. tubulin polymerisation inhibitors). Collectively, our studies provide new biological insights into genetic regulation of BP with potential to drive clinical translation in hypertension.

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Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets

Abstract

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Other files and links

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Summary statistics of UK Biobank blood pressure genome-wide association studies (GWAS) using 337,422 unrelated white European individuals

Sample-size-balanced Genotype-Tissue Expression (GTEx) v8 prediction models for transcriptome-wide association studies (TWAS)

Normalised gene expression, miRNA expression and urinary transcriptomic data from Human Kidney Tissue Resource (HKTR)

Cite this

Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Datasets

Summary statistics of UK Biobank blood pressure genome-wide association studies (GWAS) using 337,422 unrelated white European individuals

Sample-size-balanced Genotype-Tissue Expression (GTEx) v8 prediction models for transcriptome-wide association studies (TWAS)

Normalised gene expression, miRNA expression and urinary transcriptomic data from Human Kidney Tissue Resource (HKTR)

Cite this