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

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 characterise the effects of BP index variants from genome-wide association studies (GWAS) 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 colocalisation and Mendelian randomisation analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomisation we uncovered effects of BP on renal outcomes commonly affecting hypertensive patients. 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.

Methods
Please see the Methods section of the associated publication for full details.

Gene expression and alternative splicing data are derived from poly-A RNA-sequencing.

DNA methylation data are derived from the Illumina Infinium HumanMethylation450 BeadChip.

All data sets are the normalised values used for QTL testing with FastQTL.

All values have been quantile normalised and transformed by the rank-based inverse normal method.