Abstract
Hypertension, or persistently elevated blood pressure, affects about one third of the adult population worldwide and causes approximately 8.5 million deaths annually. Family studies have demonstrated that blood pressure shows substantial heritability, suggesting that genetic factors contribute to hypertension. Linkage studies and next-generation sequencing efforts have identified several variants with large effect sizes that cause rare monogenic hypertension syndromes. These syndromes often present with early onset and typically affect adrenal and renal regulation of salt reabsorption. In addition, somatic (tumour-specific) mutations have been identified in hormone-producing tumours that cause hypertension (phaeochromocytomas, aldosterone-producing adenomas, cortisol-producing adenomas, pituitary adenomas, reninomas). However, most cases of hypertension are polygenic. Large genome-wide association studies have identified many variants with small effect sizes that add to our understanding of blood pressure as a complex trait. Epigenetic mechanisms also influence gene expression and contribute to blood-pressure alterations. Several proteins that are affected by Mendelian diseases are targets of existing antihypertensive drugs and other such proteins may be good candidates for future drug development.
Key points
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Blood pressure is determined by the interplay of genetic factors — including rare variants with large effect sizes that cause monogenic hypertension syndromes and common variants with small effect sizes that contribute to polygenic cases of hypertension — and non-genetic factors such as diet and the microbiome; estimates suggest that the heritability of blood pressure is 30–50%.
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Mendelian diseases are rare causes of hypertension; most monogenic causes of hypertension affect renal salt handling and its regulation, although monogenic forms that affect the vasculature have also been identified.
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Somatic variants that cause hypertension have been identified in hormone-producing tumours of the adrenal gland, pituitary gland, extra-adrenal sympathetic or parasympathetic ganglia and renin-secreting cells of the kidney; some of these variants overlap with Mendelian disease genes.
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Common variants that are associated with blood pressure in genome-wide association studies implicate the kidney, adrenal gland and vasculature in the development of hypertension; progress has been made in identifying the causal roles of these variants.
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Epigenetic mechanisms can also influence gene expression and contribute to the development of hypertension in humans and animal models.
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Monogenic disease genes and hypertension-associated variants identified in GWAS provide important insights into the pathophysiology of hypertension and are potential targets for the development of novel antihypertensive agents.
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Change history
11 May 2026
A Correction to this paper has been published: https://doi.org/10.1038/s41581-026-01088-8
References
Kreutz, R. et al. 2024 European Society of Hypertension clinical practice guidelines for the management of arterial hypertension. Eur. J. Intern. Med. 126, 1–15 (2024).
McEvoy, J. W. et al. 2024 ESC guidelines for the management of elevated blood pressure and hypertension. Eur. Heart J. 45, 3912–4018 (2024).
Writing Committee, M. et al. 2025 AHA/ACC/AANP/AAPA/ABC/ACCP/ACPM/AGS/AMA/ASPC/NMA/PCNA/SGIM Guideline for the prevention, detection, evaluation and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. Circulation 152, e114–e218 (2025).
NCD Risk Factor Collaboration Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet 398, 957–980 (2021).
GBD 2019 Risk Factors Collaborators Global burden of 87 risk factors in 204 countries and territories, 1990-2019: a systematic analysis for the global burden of disease study 2019. Lancet 396, 1223–1249 (2020).
Forouzanfar, M. H. et al. Global burden of hypertension and systolic blood pressure of at least 110 to 115 mm Hg, 1990–2015. JAMA 317, 165–182 (2017).
Lewington, S. et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360, 1903–1913 (2002).
Rios, F. J., Montezano, A. C., Camargo, L. L. & Touyz, R. M. Impact of environmental factors on hypertension and associated cardiovascular disease. Can. J. Cardiol. 39, 1229–1243 (2023).
Charchar, F. J. et al. Lifestyle management of hypertension: International Society of Hypertension position paper endorsed by the World Hypertension League and European Society of Hypertension. J. Hypertens. 42, 23–49 (2024).
O’Donnell, J. A., Zheng, T., Meric, G. & Marques, F. Z. The gut microbiome and hypertension. Nat. Rev. Nephrol. 19, 153–167 (2023).
Luft, F. C. Twins in cardiovascular genetic research. Hypertension 37, 350–356 (2001).
Padmanabhan, S., Caulfield, M. & Dominiczak, A. F. Genetic and molecular aspects of hypertension. Circ. Res. 116, 937–959 (2015).
Pazoki, R. et al. Genetic predisposition to high blood pressure and lifestyle factors: associations with midlife blood pressure levels and cardiovascular events. Circulation 137, 653–661 (2018).
Mulatero, P. et al. Familial hyperaldosteronism: an European Reference Network on Rare Endocrine Conditions clinical practice guideline. Eur. J. Endocrinol. 190, G1–G14 (2024).
Adler, G. K. et al. Primary aldosteronism: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 110, 2453–2495 (2025).
Sutherland, D. J., Ruse, J. L. & Laidlaw, J. C. Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can. Med. Assoc. J. 95, 1109–1119 (1966).
Lifton, R. P. et al. A chimaeric 11 β-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 355, 262–265 (1992).
Scholl, U. I. et al. CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nat. Genet. 50, 349–354 (2018).
Fernandes-Rosa, F. L. et al. A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. Nat. Genet. 50, 355–361 (2018).
Schewe, J. et al. Elevated aldosterone and blood pressure in a mouse model of familial hyperaldosteronism with ClC-2 mutation. Nat. Commun. 10, 5155 (2019).
Choi, M. et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331, 768–772 (2011).
Scholl, U. I. et al. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proc. Natl Acad. Sci. USA 109, 2533–2538 (2012).
Scholl, U. I. et al. Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. eLife 4, e06315 (2015).
Seidel, E. et al. Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+). Proc. Natl Acad. Sci. USA 118, e2014876118 (2021).
Scholl, U. I. et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat. Genet. 45, 1050–1054 (2013).
Stolting, G. et al. Isradipine therapy in Cacna1dIle772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities. JCI Insight 8, e162468 (2023).
Ortner, N. J., Kaserer, T., Copeland, J. N. & Striessnig, J. De novo CACNA1D Ca2+ channelopathies: clinical phenotypes and molecular mechanism. Pflugers Arch. 472, 755–773 (2020).
Menabo, S. et al. Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency: functional consequences of four CYP11B1 mutations. Eur. J. Hum. Genet. 22, 610–616 (2014).
White, P. C. et al. A mutation in CYP11B1 (Arg-448–His) associated with steroid 11 beta-hydroxylase deficiency in Jews of Moroccan origin. J. Clin. Invest. 87, 1664–1667 (1991).
Auchus, R. J. Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic. J. Steroid Biochem. Mol. Biol. 165, 71–78 (2017).
Kagimoto, M., Winter, J. S., Kagimoto, K., Simpson, E. R. & Waterman, M. R. Structural characterization of normal and mutant human steroid 17 α-hydroxylase genes: molecular basis of one example of combined 17 α-hydroxylase/17,20 lyase deficiency. Mol. Endocrinol. 2, 564–570 (1988).
Mune, T., Rogerson, F. M., Nikkila, H., Agarwal, A. K. & White, P. C. Human hypertension caused by mutations in the kidney isozyme of 11 β-hydroxysteroid dehydrogenase. Nat. Genet. 10, 394–399 (1995).
Carvajal, C. A., Tapia-Castillo, A., Vecchiola, A., Baudrand, R. & Fardella, C. E. Classic and nonclassic apparent mineralocorticoid excess syndrome. J. Clin. Endocrinol. Metab. 105, dgz315 (2020).
Lu, Y. T. et al. Apparent mineralocorticoid excess: comprehensive overview of molecular genetics. J. Transl Med. 20, 500 (2022).
Geller, D. S. et al. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science 289, 119–123 (2000).
Rafestin-Oblin, M. E. et al. The severe form of hypertension caused by the activating S810L mutation in the mineralocorticoid receptor is cortisone related. Endocrinology 144, 528–533 (2003).
Vingerhoeds, A. C., Thijssen, J. H. & Schwarz, F. Spontaneous hypercortisolism without Cushing’s syndrome. J. Clin. Endocrinol. Metab. 43, 1128–1133 (1976).
Hurley, D. M. et al. Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J. Clin. Invest. 87, 680–686 (1991).
Hernandez-Ramirez, L. C. & Stratakis, C. A. Genetics of Cushing’s syndrome. Endocrinol. Metab. Clin. North. Am. 47, 275–297 (2018).
Paver, W. K. & Pauline, G. J. Hypertension and hyperpotassaemia without renal disease in a young male. Med. J. Aust. 2, 305–306 (1964).
Stokes, G. S., Gentle, J. L., Edwards, K. D. & Stewart, J. H. Syndrome of idiopathic hyperkalaemia and hypertension with decreased plasma renin activity: effects on plasma renin and aldosterone of reducing the serum potassium level. Med. J. Aust. 2, 1050–1054 (1968).
Wilson, F. H. et al. Human hypertension caused by mutations in WNK kinases. Science 293, 1107–1112 (2001).
Boyden, L. M. et al. Mutations in Kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482, 98–102 (2012).
Louis-Dit-Picard, H. et al. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat. Genet. 44, 456–460 (2012).
Furusho, T., Uchida, S. & Sohara, E. The WNK signaling pathway and salt-sensitive hypertension. Hypertens. Res. 43, 733–743 (2020).
Pagani, L. et al. Three reportedly unrelated families with Liddle syndrome inherited from a common ancestor. Hypertension 71, 273–279 (2018).
Gw, L. A familial renal disorder simulating primary aldosteronism but with negligible aldosterone secretion. Trans. Assoc. Physicians 76, 199–213 (1966).
Shimkets, R. A. et al. Liddle’s syndrome: heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel. Cell 79, 407–414 (1994).
Hansson, J. H. et al. Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome. Nat. Genet. 11, 76–82 (1995).
Salih, M. et al. A missense mutation in the extracellular domain of αENaC causes Liddle syndrome. J. Am. Soc. Nephrol. 28, 3291–3299 (2017).
Safian, R. D. & Textor, S. C. Renal-artery stenosis. N. Engl. J. Med. 344, 431–442 (2001).
Bilginturan, N., Zileli, S., Karacadag, S. & Pirnar, T. Hereditary brachydactyly associated with hypertension. J. Med. Genet. 10, 253–259 (1973).
Toka, O. et al. Childhood hypertension in autosomal-dominant hypertension with brachydactyly. Hypertension 56, 988–994 (2010).
Maass, P. G. et al. PDE3A mutations cause autosomal dominant hypertension with brachydactyly. Nat. Genet. 47, 647–653 (2015).
Ercu, M. et al. Phosphodiesterase 3A and arterial hypertension. Circulation 142, 133–149 (2020).
Rutsch, F. et al. Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat. Genet. 34, 379–381 (2003).
Nitschke, Y. et al. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am. J. Hum. Genet. 90, 25–39 (2012).
Guo, D. C. et al. Loss-of-function mutations in YY1AP1 Lead to grange syndrome and a fibromuscular dysplasia-like vascular disease. Am. J. Hum. Genet. 100, 21–30 (2017).
Rath, M. et al. Identification of pathogenic YY1AP1 splice variants in siblings with Grange syndrome by whole exome sequencing. Am. J. Med. Genet. A 179, 295–299 (2019).
Tank, A. W. & Lee Wong, D. Peripheral and central effects of circulating catecholamines. Compr. Physiol. 5, 1–15 (2015).
Turin, C. G., Crenshaw, M. M. & Fishbein, L. Pheochromocytoma and paraganglioma: germline genetics and hereditary syndromes. Endocr. Oncol. 2, R65–R77 (2022).
Burnichon, N. et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum. Mol. Genet. 19, 3011–3020 (2010).
Astuti, D. et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am. J. Hum. Genet. 69, 49–54 (2001).
Niemann, S. & Muller, U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat. Genet. 26, 268–270 (2000).
Baysal, B. E. et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287, 848–851 (2000).
Hao, H. X. et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325, 1139–1142 (2009).
Remacha, L. et al. Recurrent germline DLST mutations in individuals with multiple pheochromocytomas and paragangliomas. Am. J. Hum. Genet. 104, 651–664 (2019).
Buffet, A. et al. Germline mutations in the mitochondrial 2-oxoglutarate/malate carrier SLC25A11 gene confer a predisposition to metastatic paragangliomas. Cancer Res. 78, 1914–1922 (2018).
Lorenzo, F. R. et al. A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. J. Mol. Med. 91, 507–512 (2013).
Neumann, H. P. et al. Germ-line mutations in nonsyndromic pheochromocytoma. N. Engl. J. Med. 346, 1459–1466 (2002).
Eng, C. et al. Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas. J. Med. Genet. 32, 934–937 (1995).
Friedman, J. M. et al. Cardiovascular disease in neurofibromatosis 1: report of the NF1 Cardiovascular Task Force. Genet. Med. 4, 105–111 (2002).
Comino-Mendez, I. et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat. Genet. 43, 663–667 (2011).
Qin, Y. et al. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat. Genet. 42, 229–233 (2010).
Simon, D. B. et al. Bartter’s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat. Genet. 13, 183–188 (1996).
Simon, D. B. et al. Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel, ROMK. Nat. Genet. 14, 152–156 (1996).
Simon, D. B. et al. Mutations in the chloride channel gene, CLCNKB, cause Bartter’s syndrome type III. Nat. Genet. 17, 171–178 (1997).
Birkenhager, R. et al. Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nat. Genet. 29, 310–314 (2001).
Schlingmann, K. P. et al. Salt wasting and deafness resulting from mutations in two chloride channels. N. Engl. J. Med. 350, 1314–1319 (2004).
Laghmani, K. et al. Polyhydramnios, transient antenatal Bartter’s syndrome, and MAGED2 mutations. N. Engl. J. Med. 374, 1853–1863 (2016).
Bartter, F. C., Pronove, P., Gill, J. R. Jr. & Maccardle, R. C. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am. J. Med. 33, 811–828 (1962).
Gitelman, H. J., Graham, J. B. & Welt, L. G. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans. Assoc. Am. Physicians 79, 221–235 (1966).
Simon, D. B. et al. Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat. Genet. 12, 24–30 (1996).
Cheek, D. B. & Perry, J. W. A salt wasting syndrome in infancy. Arch. Dis. Child. 33, 252–256 (1958).
Geller, D. S. et al. Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I. Nat. Genet. 19, 279–281 (1998).
Chang, S. S. et al. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat. Genet. 12, 248–253 (1996).
Strautnieks, S. S., Thompson, R. J., Gardiner, R. M. & Chung, E. A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families. Nat. Genet. 13, 248–250 (1996).
Williams, T. A. et al. International histopathology consensus for unilateral primary aldosteronism. J. Clin. Endocrinol. Metab. 106, 42–54 (2021).
Funder, J. W. et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 101, 1889–1916 (2016).
Beuschlein, F. et al. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat. Genet. 45, 440–444 (2013).
Scholl, U. I. Genetics of primary aldosteronism. Hypertension 79, 887–897 (2022).
Azizan, E. A. et al. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat. Genet. 45, 1055–1060 (2013).
Dutta, R. K. et al. A somatic mutation in CLCN2 identified in a sporadic aldosterone-producing adenoma. Eur. J. Endocrinol. 181, K37–K41 (2019).
Nanba, K. et al. Somatic CACNA1H mutation as a cause of aldosterone-producing adenoma. Hypertension 75, 645–649 (2020).
Rege, J. et al. Somatic SLC30A1 mutations altering zinc transporter ZnT1 cause aldosterone-producing adenomas and primary aldosteronism. Nat. Genet. 55, 1623–1631 (2023).
Wu, X. et al. Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production. Nat. Genet. 55, 1009–1021 (2023).
Tadjine, M., Lampron, A., Ouadi, L. & Bourdeau, I. Frequent mutations of beta-catenin gene in sporadic secreting adrenocortical adenomas. Clin. Endocrinol. 68, 264–270 (2008).
Zhou, J. et al. Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause. Nat. Genet. 53, 1360–1372 (2021).
Nishimoto, K. et al. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc. Natl Acad. Sci. USA 112, E4591–E4599 (2015).
Omata, K. et al. Cellular and genetic causes of idiopathic hyperaldosteronism. Hypertension 72, 874–880 (2018).
Nishimoto, K. et al. Case report: nodule development from subcapsular aldosterone-producing cell clusters causes hyperaldosteronism. J. Clin. Endocrinol. Metab. 101, 6–9 (2016).
Reincke, M. & Fleseriu, M. Cushing syndrome: a review. JAMA 330, 170–181 (2023).
Reincke, M. et al. Mutations in the deubiquitinase gene USP8 cause Cushing’s disease. Nat. Genet. 47, 31–38 (2015).
Chen, J. et al. Identification of recurrent USP48 and BRAF mutations in Cushing’s disease. Nat. Commun. 9, 3171 (2018).
Hernandez-Ramirez, L. C. et al. Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing’s disease. Endocr. Relat. Cancer 24, 379–392 (2017).
Beuschlein, F. et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing’s syndrome. N. Engl. J. Med. 370, 1019–1028 (2014).
Tissier, F. et al. Mutations of β-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res. 65, 7622–7627 (2005).
Lenders, J. W. M. et al. Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension. J. Hypertens. 38, 1443–1456 (2020).
Huang, Y. C. et al. Somatic SDHA mutations in paragangliomas in siblings: case report of 2 cases. Medicine 99, e22497 (2020).
van Nederveen, F. H., Korpershoek, E., Lenders, J. W., de Krijger, R. R. & Dinjens, W. N. Somatic SDHB mutation in an extraadrenal pheochromocytoma. N. Engl. J. Med. 357, 306–308 (2007).
Weber, A., Hoffmann, M. M., Neumann, H. P. & Erlic, Z. Somatic mutation analysis of the SDHB, SDHC, SDHD, and RET genes in the clinical assessment of sporadic and hereditary pheochromocytoma. Horm. Cancer 3, 187–192 (2012).
Comino-Mendez, I. et al. Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis. Hum. Mol. Genet. 22, 2169–2176 (2013).
Gaal, J. et al. Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas. J. Clin. Endocrinol. Metab. 95, 1274–1278 (2010).
Richter, S. et al. Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma. Genet. Med. 21, 705–717 (2019).
Burnichon, N. et al. Somatic NF1 inactivation is a frequent event in sporadic pheochromocytoma. Hum. Mol. Genet. 21, 5397–5405 (2012).
Welander, J. et al. Integrative genomics reveals frequent somatic NF1 mutations in sporadic pheochromocytomas. Hum. Mol. Genet. 21, 5406–5416 (2012).
Crona, J. et al. Somatic mutations in H-RAS in sporadic pheochromocytoma and paraganglioma identified by exome sequencing. J. Clin. Endocrinol. Metab. 98, E1266–E1271 (2013).
Welander, J. et al. Activating FGFR1 mutations in sporadic pheochromocytomas. World J. Surg. 42, 482–489 (2018).
Burnichon, N. et al. Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Hum. Mol. Genet. 20, 3974–3985 (2011).
Burnichon, N. et al. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin. Cancer Res. 18, 2828–2837 (2012).
Fishbein, L. et al. Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas. Nat. Commun. 6, 6140 (2015).
Fishbein, L. et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell 31, 181–193 (2017).
Juhlin, C. C. et al. Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene. Genes. Chromosomes Cancer 54, 542–554 (2015).
Treger, T. D. et al. Targetable NOTCH1 rearrangements in reninoma. Nat. Commun. 14, 5826 (2023).
Belyea, B. C. et al. Overexpression of notch signaling in renin cells leads to a polycystic kidney phenotype. Clin. Sci. 137, 35–45 (2023).
Keaton, J. M. et al. Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits. Nat. Genet. 56, 778–791 (2024).
Levy, D. et al. Genome-wide association study of blood pressure and hypertension. Nat. Genet. 41, 677–687 (2009).
Padmanabhan, S. & Dominiczak, A. F. Genomics of hypertension: the road to precision medicine. Nat. Rev. Cardiol. 18, 235–250 (2021).
Newton-Cheh, C. et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat. Genet. 41, 666–676 (2009).
Evangelou, E. et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat. Genet. 50, 1412–1425 (2018).
Giri, A. et al. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. Nat. Genet. 51, 51–62 (2019).
Yang, J., Zeng, J., Goddard, M. E., Wray, N. R. & Visscher, P. M. Concepts, estimation and interpretation of SNP-based heritability. Nat. Genet. 49, 1304–1310 (2017).
Genin, E. Missing heritability of complex diseases: case solved? Hum. Genet. 139, 103–113 (2020).
Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).
Ives, C. W., Sinkey, R., Rajapreyar, I., Tita, A. T. N. & Oparil, S. Preeclampsia-pathophysiology and clinical presentations: JACC state-of-the-art review. J. Am. Coll. Cardiol. 76, 1690–1702 (2020).
Honigberg, M. C. et al. Polygenic prediction of preeclampsia and gestational hypertension. Nat. Med. 29, 1540–1549 (2023).
Freund, M. K. et al. Phenotype-specific enrichment of mendelian disorder genes near GWAS regions across 62 complex traits. Am. J. Hum. Genet. 103, 535–552 (2018).
Xu, X. et al. Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets. Nat. Commun. 15, 2359 (2024).
Padmanabhan, S. et al. Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension. PLoS Genet. 6, e1001177 (2010).
Graham, L. A. et al. Validation of uromodulin as a candidate gene for human essential hypertension. Hypertension 63, 551–558 (2014).
Alexander, M. R. et al. A single nucleotide polymorphism in sh2b3/lnk promotes hypertension development and renal damage. Circ. Res. 131, 731–747 (2022).
Oliveros, W. et al. Systematic characterization of regulatory variants of blood pressure genes. Cell Genom. 3, 100330 (2023).
Kato, N. et al. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation. Nat. Genet. 47, 1282–1293 (2015).
Gunawardhana, K. L. et al. A systems biology approach identifies the role of dysregulated PRDM6 in the development of hypertension. J. Clin. Investig. 133, e160036 (2023).
Gupta, R. M. et al. A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell 170, 522–533 (2017).
Broekema, R. V., Bakker, O. B. & Jonkers, I. H. A practical view of fine-mapping and gene prioritization in the post-genome-wide association era. Open Biol. 10, 190221 (2020).
Degner, K. N., Bell, J. L., Jones, S. D. & Won, H. Just a SNP away: The future of in vivo massively parallel reporter assay. Cell Insight 4, 100214 (2025).
Eales, J. M. et al. Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney. Nat. Genet. 53, 630–637 (2021).
Wang, Q. et al. Rare variant contribution to human disease in 281,104 UK Biobank exomes. Nature 597, 527–532 (2021).
Backman, J. D. et al. Exome sequencing and analysis of 454,787 UK Biobank participants. Nature 599, 628–634 (2021).
Kelly, T. N. et al. Insights from a large-scale whole-genome sequencing study of systolic blood pressure, diastolic blood pressure, and hypertension. Hypertension 79, 1656–1667 (2022).
Copeland, I. et al. Exome sequencing implicates ancestry-related Mendelian variation at SYNE1 in childhood-onset essential hypertension. JCI Insight 9, e172152 (2024).
Pei, F. et al. Differential expression and DNA methylation of angiotensin type 1A receptors in vascular tissues during genetic hypertension development. Mol. Cell Biochem. 402, 1–8 (2015).
Lee, H. A. et al. Promoter hypomethylation upregulates Na+-K+-2Cl− cotransporter 1 in spontaneously hypertensive rats. Biochem. Biophys. Res. Commun. 396, 252–257 (2010).
Lee, H. A. et al. Tissue-specific upregulation of angiotensin-converting enzyme 1 in spontaneously hypertensive rats through histone code modifications. Hypertension 59, 621–626 (2012).
Bogdarina, I., Welham, S., King, P. J., Burns, S. P. & Clark, A. J. Epigenetic modification of the renin-angiotensin system in the fetal programming of hypertension. Circ. Res. 100, 520–526 (2007).
Alexander, M. R., Edwards, T. L. & Harrison, D. G. GWAS for defining the pathogenesis of hypertension: have they delivered? Hypertension 82, 573–582 (2025).
Williams, B. et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 386, 2059–2068 (2015).
Flack, J. M. et al. Efficacy and safety of baxdrostat in uncontrolled and resistant hypertension. N. Engl. J. Med. 393, 1363–1374 (2025).
Nelson, M. R. et al. The support of human genetic evidence for approved drug indications. Nat. Genet. 47, 856–860 (2015).
Etges, A. et al. A novel homozygous KLHL3 mutation as a cause of autosomal recessive pseudohypoaldosteronism type II diagnosed late in life. Nephron 146, 418–428 (2022).
Constantinescu, G. et al. Integration of artificial intelligence and plasma steroidomics with laboratory information management systems: application to primary aldosteronism. Clin. Chem. Lab. Med. 60, 1929–1937 (2022).
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Rockefeller University has filed a patent application (PCT/US2018/033362, Compositions and methods for diagnosing and treating diseases and disorders associated with mutant KCNJ5), listing U.I.S. as an inventor. The other authors declare no competing interests.
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Supplementary information
Glossary
- Missing heritability
-
The difference between the heritability of a trait or disease that can be explained by variants identified in genome-wide association studies and heritability estimates from family studies. Such missing heritability has been observed for many traits and diseases.
- Monogenic disorders
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Disorders that are caused by a mutation in a single gene. Also known as Mendelian diseases.
- Polygenic disorders
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Disorders that are caused by the combined effect of multiple variants in different genes.
- Sentinel SNP
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The SNP at a particular locus that has the strongest association with a trait (lowest P value) in a genome-wide association study.
- Unequal crossing-over
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A homologous recombination event that occurs between different genetic loci with similar sequences during meiosis and can result in gene duplication or deletion.
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Stölting, G., Tran Vo, K.N., Haus, J. et al. The genetics of hypertension. Nat Rev Nephrol 22, 137–151 (2026). https://doi.org/10.1038/s41581-025-01020-6
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DOI: https://doi.org/10.1038/s41581-025-01020-6
