Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney
- Eales J. M.
- Jiang X.
- Xu X.
- Saluja S.
- Akbarov A.
- Cano-Gamez E.
- McNulty M. T.
- Finan C.
- Guo H.
- Wystrychowski W.
- Szulinska M.
- Thomas H. B.
- Pramanik S.
- Chopade S.
- Prestes P. R.
- Wise I.
- Evangelou E.
- Salehi M.
- Shakanti Y.
- Ekholm M.
- Denniff M.
- Nazgiewicz A.
- Eichinger F.
- Godfrey B.
- Antczak A.
- Glyda M.
- Krol R.
- Eyre S.
- Brown J.
- Berzuini C.
- Bowes J.
- Caulfield M.
- Zukowska-Szczechowska E.
- Zywiec J.
- Bogdanski P.
- Kretzler M.
- Woolf A. S.
- Talavera D.
- Keavney B.
- Maffia P.
- Guzik T. J.
- O'Keefe R. T.
- Trynka G.
- Samani N. J.
- Hingorani A.
- Sampson M. G.
- Morris A. P.
- Charchar F. J.
- Tomaszewski M.
DOIAbstract
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. Thr...
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