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

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Sushant Saluja
  • Artur Akbarov
  • Eddie Cano-Gomez
  • Michelle T. McNulty
  • Christopher Finan
  • Wojciech Wystrychowski
  • Monika Szulinska
  • Huw Thomas
  • Sanjeev Pramanik
  • Sandesh Chopade
  • Priscella R. Prestes
  • Ingrid Wise
  • Evangelos Evangelou
  • Mahan Salehi
  • Yusif Shakanti
  • Mikael Ekholm
  • Matthew Denniff
  • Felix Eichinger
  • Bradley Godfrey
  • Andrzej Antczak
  • Maciej Glyda
  • Robert Król
  • Stephen Eyre
  • Jason Brown
  • Carlo Berzuini
  • John Bowes
  • Mark Caulfield
  • Ewa Zukowska-Szczechowska
  • Joanna Zywiec
  • Pawel Bogdanski
  • Matthias Kretzler
  • Adrian S. Woolf
  • David Talavera
  • Bernard Keavney
  • Pasquale Maffia
  • Tomasz J. Guzik
  • Raymond O'Keefe
  • Gosia Trynka
  • Nilesh J Samani
  • Aroon D. Hingorani
  • Matthew G. Sampson
  • Andrew P. Morris
  • Fadi J. Charchar
  • Maciej Tomaszewski
  • Andrew Morris

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.

Bibliographical metadata

Original languageEnglish
Pages (from-to)630–637
Number of pages8
JournalNature Genetics
Volume53
Issue number5
DOIs
Publication statusPublished - 6 May 2021