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 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.

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References

Beaney T, Schutte A, Tomaszewski M, Ariti C, Burrell L, Castillo R . May Measurement Month 2017: an analysis of blood pressure screening results worldwide. Lancet Glob Health. 2018; 6(7):e736-e743. DOI: 10.1016/S2214-109X(18)30259-6. View

Lim S, Vos T, Flaxman A, Danaei G, Shibuya K, Adair-Rohani H . A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012; 380(9859):2224-60. PMC: 4156511. DOI: 10.1016/S0140-6736(12)61766-8. View

Doris P . The genetics of blood pressure and hypertension: the role of rare variation. Cardiovasc Ther. 2010; 29(1):37-45. PMC: 3562708. DOI: 10.1111/j.1755-5922.2010.00246.x. View

Evangelou E, Warren H, Mosen-Ansorena D, Mifsud B, Pazoki R, Gao H . Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat Genet. 2018; 50(10):1412-1425. PMC: 6284793. DOI: 10.1038/s41588-018-0205-x. View

Warren H, Evangelou E, Cabrera C, Gao H, Ren M, Mifsud B . Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Nat Genet. 2017; 49(3):403-415. PMC: 5972004. DOI: 10.1038/ng.3768. View

Giri A, Hellwege J, Keaton J, Park J, Qiu C, Warren H . Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. Nat Genet. 2018; 51(1):51-62. PMC: 6365102. DOI: 10.1038/s41588-018-0303-9. View

Cabrera C, Ng F, Warren H, Barnes M, Munroe P, Caulfield M . Exploring hypertension genome-wide association studies findings and impact on pathophysiology, pathways, and pharmacogenetics. Wiley Interdiscip Rev Syst Biol Med. 2015; 7(2):73-90. DOI: 10.1002/wsbm.1290. View

Ehret G, Munroe P, Rice K, Bochud M, Johnson A, Chasman D . Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011; 478(7367):103-9. PMC: 3340926. DOI: 10.1038/nature10405. View

Surendran P, Drenos F, Young R, Warren H, Cook J, Manning A . Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension. Nat Genet. 2016; 48(10):1151-1161. PMC: 5056636. DOI: 10.1038/ng.3654. View

10.

Ehret G, Ferreira T, Chasman D, Jackson A, Schmidt E, Johnson T . The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet. 2016; 48(10):1171-1184. PMC: 5042863. DOI: 10.1038/ng.3667. View

11.

Liu C, Kraja A, Smith J, Brody J, Franceschini N, Bis J . Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. Nat Genet. 2016; 48(10):1162-70. PMC: 5320952. DOI: 10.1038/ng.3660. View

12.

Hoffmann T, Ehret G, Nandakumar P, Ranatunga D, Schaefer C, Kwok P . Genome-wide association analyses using electronic health records identify new loci influencing blood pressure variation. Nat Genet. 2016; 49(1):54-64. PMC: 5370207. DOI: 10.1038/ng.3715. View

13.

Do C, Lang C, Lin J, Darbary H, Krupska I, Gaba A . Mechanisms and Disease Associations of Haplotype-Dependent Allele-Specific DNA Methylation. Am J Hum Genet. 2016; 98(5):934-955. PMC: 4863666. DOI: 10.1016/j.ajhg.2016.03.027. View

14.

Do C, Shearer A, Suzuki M, Terry M, Gelernter J, Greally J . Genetic-epigenetic interactions in cis: a major focus in the post-GWAS era. Genome Biol. 2017; 18(1):120. PMC: 5477265. DOI: 10.1186/s13059-017-1250-y. View

15.

Park E, Pan Z, Zhang Z, Lin L, Xing Y . The Expanding Landscape of Alternative Splicing Variation in Human Populations. Am J Hum Genet. 2018; 102(1):11-26. PMC: 5777382. DOI: 10.1016/j.ajhg.2017.11.002. View

16.

Smith A, Kilaru V, Kocak M, Almli L, Mercer K, Ressler K . Methylation quantitative trait loci (meQTLs) are consistently detected across ancestry, developmental stage, and tissue type. BMC Genomics. 2014; 15:145. PMC: 4028873. DOI: 10.1186/1471-2164-15-145. View

17.

Raj T, Li Y, Wong G, Humphrey J, Wang M, Ramdhani S . Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer's disease susceptibility. Nat Genet. 2018; 50(11):1584-1592. PMC: 6354244. DOI: 10.1038/s41588-018-0238-1. View

18.

Jiang X, Eales J, Scannali D, Nazgiewicz A, Prestes P, Maier M . Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney. Eur Heart J. 2020; 41(48):4580-4588. PMC: 7665509. DOI: 10.1093/eurheartj/ehaa794. View

19.

Xu X, Eales J, Akbarov A, Guo H, Becker L, Talavera D . Molecular insights into genome-wide association studies of chronic kidney disease-defining traits. Nat Commun. 2018; 9(1):4800. PMC: 6250666. DOI: 10.1038/s41467-018-07260-4. View

20.

Rowland J, Akbarov A, Eales J, Xu X, Dormer J, Guo H . Uncovering genetic mechanisms of kidney aging through transcriptomics, genomics, and epigenomics. Kidney Int. 2019; 95(3):624-635. PMC: 6390171. DOI: 10.1016/j.kint.2018.10.029. View