Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney

Eales, James M., Jiang, Xiao, Xu, Xiaoguang, Saluja, Sushant, Akbarov, Artur, Cano-Gamez, Eddie, McNulty, Michelle T., Finan, Christopher, Guo, Hui, Wystrychowski, Wojciech, Szulinska, Monika, Thomas, Huw B., Pramanik, Sanjeev, Chopade, Sandesh, Prestes, Priscilla R., Wise, Ingrid, Evangelou, Evangelos, Salehi, Mahan, Shakanti, Yusif, Ekholm, Mikael, Denniff, Matthew, Nazgiewicz, Alicja, Eichinger, Felix, Godfrey, Bradley, Antczak, Andrzej, Glyda, Maciej, Król, Robert, Eyre, Stephen, Brown, Jason, Berzuini, Carlo, Bowes, John, Caulfield, Mark, Zukowska-Szczechowska, Ewa, Zywiec, Joanna, Bogdanski, Pawel, Kretzler, Matthias, Woolf, Adrian S., Talavera, David, Keavney, Bernard, Maffia, Pasquale, Guzik, Tomasz J., O’Keefe, Raymond T., Trynka, Gosia, Samani, Nilesh J., Hingorani, Aroon, Sampson, Matthew G., Morris, Andrew P., Charchar, Fadi J., and Tomaszewski, Maciej (2021) Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney. Nature Genetics, 53 (5). pp. 630-637.

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Abstract

The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.

Item ID: 70420
Item Type: Article (Research - C1)
ISSN: 1546-1718
Copyright Information: Copyright © 2021, Crown. This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1038/s41588-021-00835-w
Research Data: https://doi.org/10.5061/dryad.15dv41nvx
Date Deposited: 09 May 2022 23:58
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