Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney.
AuthorsEales, James M; orcid: 0000-0001-6238-5952
Jiang, Xiao; orcid: 0000-0002-1442-8927
Xu, Xiaoguang; orcid: 0000-0003-4568-1623
McNulty, Michelle T
Finan, Christopher; orcid: 0000-0002-3319-1937
Guo, Hui; orcid: 0000-0003-0282-6933
Szulinska, Monika; orcid: 0000-0002-1163-0919
Thomas, Huw B; orcid: 0000-0001-9626-9706
Pramanik, Sanjeev; orcid: 0000-0003-2317-3628
Prestes, Priscilla R; orcid: 0000-0002-9034-6595
Evangelou, Evangelos; orcid: 0000-0002-5488-2999
Salehi, Mahan; orcid: 0000-0002-4064-4762
Eyre, Stephen; orcid: 0000-0002-1251-6974
Berzuini, Carlo; orcid: 0000-0001-6056-0489
Bowes, John; orcid: 0000-0003-4659-031X
Caulfield, Mark; orcid: 0000-0001-9295-3594
Woolf, Adrian S; orcid: 0000-0001-5541-1358
Talavera, David; orcid: 0000-0002-8820-3931
Keavney, Bernard; orcid: 0000-0001-9573-0812
Maffia, Pasquale; orcid: 0000-0003-3926-4225
Guzik, Tomasz J; orcid: 0000-0002-5039-7849
O'Keefe, Raymond T; orcid: 0000-0001-8764-1289
Trynka, Gosia; orcid: 0000-0002-6955-9529
Samani, Nilesh J
Hingorani, Aroon; orcid: 0000-0001-8365-0081
Sampson, Matthew G; orcid: 0000-0001-9560-076X
Morris, Andrew P
Charchar, Fadi J; orcid: 0000-0002-6164-9941
Tomaszewski, Maciej; orcid: 0000-0001-8215-6567; email: email@example.com
MetadataShow full item record
AbstractThe 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.
CitationNature genetics, volume 53, issue 5, page 630-637
DescriptionFrom PubMed via Jisc Publications Router
History: received 2020-01-10, accepted 2021-03-04
Publication status: ppublish
Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH); Grant(s): R01 DK117445-01A1
Funder: NIDDK NIH HHS; Grant(s): R01 DK108805, R01 DK119380, R01 DK108805, R01 DK119380
Funder: Kidney Research UK; Grant(s): RP_017_20180302
Funder: Gates Cambridge Trust; Grant(s): OPP1144
Funder: British Heart Foundation (BHF); Grant(s): PG/19/16/34270, CH/13/2/30154, PG/19/84/34771
Funder: Wellcome Trust (Wellcome); Grant(s): WT206194
Funder: RCUK | Medical Research Council (MRC); Grant(s): MR/R010900/1
Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); Grant(s): ERC-CoG-Inflammatension 726318
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