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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Hypertension. Author manuscript; available in PMC 2014 January 9.
Published in final edited form as:
PMCID: PMC3885905

Report of the National Heart, Lung and Blood Institute Working Group on Epigenetics and Hypertension

Human and financial impact of essential hypertension

Hypertension, defined as a condition associated with ≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure, affects over one billion people worldwide1 and in 2009 it cost the US health care system more than $73 billion2. Despite the availability of many anti-hypertensive therapies, individual responses vary and efficacy remains a concern. Current treatments have yielded only modest reductions in the overall disease risk even in countries where therapeutics are available and affordable. The initiating causes and the pathogenic mechanisms for disease and its comorbidities remain largely unknown, and prognostic markers for adult hypertension that could improve its diagnosis, prevention, and ultimately its management are not yet available. As a result, nearly 28% of the US population and a similar proportion of the adult Western European and Canadian populations suffer from what is known as “essential hypertension”3, which is a primary component of several complex, multifactorial, multigenic conditions that are commonly associated with high levels of morbidity and mortality from diabetes, cardiovascular and renal disease. If the current rise in the number of hypertension cases is not abated, total annual global healthcare costs resulting from suboptimal blood pressure for those older than 30 years of age could amount to $3.6 trillion over the next 10 years4.

Genetics, “Missing Heritability” and the Epigenetic Hypothesis

The causes of essential hypertension remain poorly understood even though the complex mechanisms for blood pressure (BP) regulation have been extensively characterized in both humans and animal models5,6,7. Comprehensive study of more than a dozen inbred rat strains that recapitulate many aspects of hereditary human hypertension has added substantially throughout the years to our understanding of the underlying physiological and molecular pathways, the genetic complexity of risk and treatment responses, as well as the pathological consequences of hypertension8. In fact, many interventions that lead to a lowering of blood pressure were identified first with these experimental model systems9,10. Detailed annotations of such experimental models are currently available (PhysGen Knockout Program, These studies in experimental models are however only the first step in the quest to clarify the genetic and phenotypic architecture of this complex human disease11,12,13,14,15.

Hypertension is a highly heritable trait16,17 and recent genome-wide linkage and association studies (GWAS) as well as candidate gene approaches clearly demonstrate the multigenic complexity of essential hypertension18,19,20,21,22. The International Consortium for Blood Pressure Genome-Wide Association Studies, which used a multistage design in 200,000 individuals of European descent, recently identified 16 novel functional genetic variants, associated with high blood pressure in human populations20. (These variants are commonly known as quantitative trait loci, or QTLs.) Six of these loci involve genes previously known or suspected to regulate blood pressure, with the other genetic variants pointing to novel pathways that influence blood pressure and cardiovascular disease risk.

An unexpected and disconcerting observation from these genetic studies is that the discovered genetic variants, individually and collectively, account for only a small fraction of phenotypic variation and disease risk. For example, these blood pressure QTLs together account for only a small proportion of BP variation (up to 5 mmm Hg), yet their typical effect size is sufficient to raise cardiovascular disease risk in human populations18,19,20,21,22. Importantly, although the CHARGE and GlobalBPgen consortia established and replicated the effects of 8 novel loci on BP, the cumulative effect of these 8 loci explained only ~1% of BP variance18,19. These results are especially surprising given the substantial heritability of BP, estimated between 30% and 40%15,16. Similar results have emerged in GWAS of other complex conditions in humans and genetic studies of other species11,12,13,14,15. This difference between estimated and observed variance is termed ‘missing heritability’, the search for which has now become one of the primary goals for research on hypertension and other complex conditions11.

To explain the ‘missing heritability’ of complex traits, several hypotheses have been proposed, including over-estimates of heritability, unexplored regions of the genome, untested classes of genetic variants, the action of many rare genetic variants, and gene interactions11,23,24. Phenotypic variation can also be regulated independently of changes in DNA sequence, thereby escaping detection with classical genetic approaches25,26,27,28,29,30,31. These heritable epigenetic changes could explain some of the ‘missing heritability’ in hypertension, and some circumstantial evidence involving modification of genes that could affect important pathways in hypertension is beginning to emerge, further prompting the need for experiments specifically designed to prove a causal relationship32.


Epigenetics is defined as the transmission from one cell generation to the next (through mitosis) or from one organismal generation to the next (through meiosis) of gene expression patterns that do not rely explicitly on differences in DNA sequence25. The term was originally introduced to account for the maintenance of cell- and tissue-specific gene expression patterns across mitotic cell divisions throughout somatic development. Many cell functions such as tissue-specificity, germline-specificity, imprinting and X-chromosome inactivation, rely on correct epigenetic control of gene expression30,31. Introduction of high-throughput technologies, which now enable epigenetic features to be comprehensively and quantitatively profiled across the genome, has led to exciting evidence in animal models where epigenetic changes have been documented not only during development but also in adult conditions such as cancer33, cardiovascular disease34, diabetes35, obesity36, and longevity37. Evidence for epigenetic effects in humans is more limited because of the considerable challenges in study design needed to reliably distinguish the various sources of phenotypic variation. As a result, many questions remain, such as defining the environmental and genetic factors that trigger epigenetic changes, defining the molecular mechanisms that maintain and where necessary reverse epigenetic features, assessing the relative contributions of genetic, environmental and epigenetic factors, and characterizing the impact of epigenetic changes on phenotypic variation and disease risk within and across generations.

Epigenetic changes are orchestrated by several molecular processes, including nucleic acid methylation, histone modification, nucleosome positioning, transcription control with DNA binding proteins and noncoding RNAs, and translation control with microRNAs and RNA binding proteins26,27,28,29,30,31. Of the many modes of epigenetic control, the best studied are histone modification and DNA methylation. Histone modification is an important mechanism that leads to changes in the nucleosome to constrain DNA wrapping around its histone core (nucleosome positioning). Chemical modification of the N-terminal tails of histone proteins forms a “histone code” that regulates gene activity. DNA methylation is another important mechanism of epigenetic control in which methylation of DNA occurs at the cytosine base of DNA, often in the context of CpG dinucleotides. In addition, other forms of chemically modified DNA have recently been reported26. An important but less studied mode of epigenetic control involves noncoding-RNAs (microRNAs as well as other long and short RNAs) that regulate gene expression and mRNA translation. Systematically characterizing these various kinds of epigenetic marks across the genome, during development and throughout the life of an organism, is a major challenge, as is dealing with cellular and temporal heterogeneity in these marks.

Studies in experimental animals show that epigenetic changes can arise throughout life, from early embryos to old age, as a result of developmental and physiological processes, environmental exposure, and stochastic events. The epigenome is thought to be most vulnerable to modification during embryogenesis when DNA synthesis is rapid and when both DNA methylation patterns and chromatin structure required for normal development are established. During development for example, maternal nutritional status as well as altered hormonal and stress profiles can profoundly affect epigenetic features with long-term impacts on disease risk. In addition, studies in twins at different ages show that, although identical at birth, the epigenome diverges during lifetime38. An understanding of the mechanisms that transmit environmental and genetic signals to the molecular machinery responsible for epigenetic changes that will undoubtedly emerge would mechanistically explain the molecular embedding of early childhood experiences (“nurture”) onto the genome (“nature”)39.

In many organisms, some epigenetic changes are not erased during gametogenesis and can affect the phenotype and health not only of immediate offspring, but also of future generations through transgenerational effects27,28,29,30,40,41,42,43,44,45,46,47,48. Several studies in rodents and other species have revealed remarkable evidence for heritable epigenetic changes where the phenotypic effects of environmental exposure and genetic variants can be transmitted epigenetically across multiple generations. In some circumstances, these effects can be as strong as conventional genetic effects, endure across multiple generations, transmit through the male or the female germ-lineage, and reverse under certain conditions44,45. Epigenetic inheritance is usually determined by a combination of genetically-controlled susceptibility of the parental genome to various stressors and the vulnerability of the offspring’s genome to these inherited epigenetic changes. Such changes enable homeostatic adaptations of the epigenetic code in response to various environmental and genetic stressors within a parent’s lifetime to be communicated to the offspring as “preadaptations” to the particular environment in which they live and the family to which they belong27,28,49,50,51,52.

Role of epigenetics in hypertension

Many questions emerge from these considerations: Are epigenetic marks and features a cause or consequence of hypertension? Do epigenetic changes contribute to comorbidities of hypertension such as diabetes, cardiovascular and renal disease? Are epigenetic features indicative prognostic or diagnostic biomarkers for human hypertension? Are epigenetic marks of hypertension fixed early in life rather than changing dynamically in response to various perturbations? To what extent are these epigenetic features reversible in a general or in a targeted manner? What is the molecular basis for epigenetic memory related to hypertension within and across multiple generations, how are these marks established, and how do they differ from other epigenetic features?

In parallel with studying conventional epigenetic features such as methylation profiles and histone modification, important insights could be gained from investigating the effects of environmental perturbations on mRNA, microRNA and non-coding RNA expression patterns, and their potential associations with the physiological changes during tissue and organ development as well as disease initiation and progression.

The Working Group prioritized three questions that require immediate attention:

  1. Do epigenetic changes affect blood pressure in humans? A deeper understanding of epigenetic changes in response to environmental and genetic stresses is needed to generate hypothesis-driven experimental studies that can in turn establish causality as well as reveal fundamental molecular mechanisms of blood pressure regulation. For instance, studies are urgently needed to establish the chronological sequence of epigenetic and pathological changes at different life-stages (preconception, conception, development, birth, childhood, adolescence and adulthood) both during normal development and during the onset and progression of hypertension. With model organisms, experiments can be designed to rigorously characterize all life-stages, obtain diverse organs and tissues for analysis, and control age, sex, and environment factors. In parallel, human studies could examine phenotypic discordances within monozygotic (identical) twin pairs, which may provide a unique window into epigenetic control of blood pressure. Comparative genetic studies need to take advantage of the strong evolutionary conservation of DNA methylation and histone folding in species such as rats, mice, rhesus monkeys and humans53. Epigenetic marks that are not shared among humans and animal models could point to biological pathways and molecular mechanisms that may be highly relevant to human hypertension. Finally, advantage should be taken of the rich resources of inbred rodent models of hypertension and well-characterized consomic, congenic and recombinant inbred strains in which many allelic variants have been captured. Together these integrated studies are essential to establish basic principles of epigenetic mechanisms in health and disease as well as to meaningfully translate epigenetic research into clinical practice.
  2. What are the relative contributions of epigenetic, genetic and environmental factors to the development of hypertension and its comorbidities? Assessing the relative contribution of genetic, epigenetic and environmental factors to hypertension is urgently needed. Studying large families in which hypertension segregates in members exposed to similar environments and diets would be highly informative. For instance, answers could be sought by investigating several large, genetically and phenotypically characterized human cohorts together with family and twin studies to establish the patterns of covariation among genetic variants, epigenetic factors, and physiological phenotypes. Monozygotic (identical) and dizygotic (fraternal) twin studies allow estimation of the role of heredity on determination of many traits54. Perturbations that provoke disease, together with modeling of the molecular and physiological networks and pathways aimed at predicting, identifying and manipulating causality factors, will be key elements in these studies. Such approaches need to distinguish between epigenetic changes that may be simply indicative of disease, e.g., diagnostic markers, versus those playing a causal role in the development and maintenance of hypertension in response to specific environmental challenges. Parallel studies in several different environments with various perturbations will be needed in both animal models and humans to establish general versus context-dependent relationships. All these provide good opportunities to quantify the relative contributions of genetic variants and epigenetic factors to various forms of essential hypertension that can be addressed under defined environmental conditions.
  3. Are epigenetic changes related to hypertension heritable, do they accumulate across generations, and can they be reversed? Recent evidence shows transgenerational inheritance of environmental and genetic influences on diverse phenotypes and disease risks. Considerable epidemiological and experimental evidence in model organisms and to a lesser extent in humans show that the consequences of environmental exposures and genetic variants can be transmitted for at least several generations after exposure. Under these conditions establishing the origins of disease resulting from the action of genetic variants in ancestral generations would be difficult to detect among affected individuals in a traditional GWAS. In addition to contributing to hypertension risk, heritable epigenetic changes may accumulate across generations and could account for the dramatic increase in hypertension, obesity and related metabolic conditions. Animal models are especially important to establish principles of study design, candidate molecular features, and relevant physiological functions to validate in humans. Genotype-phenotype associations could also be tested across generations in selected human populations.

The WG recognizes that these proposals raise considerable challenges. Epigenetic studies, especially those that involve transgenerational effects, will be complicated in humans because of issues related to study design, statistical power, environmental and genetic heterogeneity among families and populations, and the dynamic nature of epigenetic changes compared to the stability of DNA sequences. Studies with animal models face similar challenges. In addition, physiological and pharmacological research has made important contributions to treatment, and studies of both monogenic and multigenic variation have provided important insights about molecular functions and pathogenic mechanisms. But substantial problems remain for BP management. Integrating epigenetic studies with ongoing studies may lead to breakthroughs in our understanding of BP control.

Current needs, resources, and future directions of research

The NHLBI Working Group identified a remarkable number of currently existing molecular, genomic, physiological and computational tools and approaches that could meaningfully move this field forward. The WG also identified several important technology needs.

Over the past decade many genomic and proteomic databases and technologies have been developed. These databases enable systematic collection, storage, and distribution for research of tissues and cells. Appropriate databases of patient information, including their genetics, lifestyle, clinical history, and other relevant information, have also emerged. Similar databases are related to studies of model organisms so that efficient comparative analyses are increasingly feasible. Numerous experimental models are already available and continue to be developed as information resources for many aspects of mouse genetics and biology, including the NIH-funded initiative the “Knockout Mouse Project” (KOMP), the Mouse Genome Database (, and the Mouse Phenome Database ( The Rat Genome Database ( contains all of the genomic rat model systems including inbred, consomic and knockout strains. Other resources help researchers identify appropriate model organisms, e.g. “Link Animal Models to Human Disease” (LAMHDI) (, existing clinical cohorts (e.g., or access other information relevant for the relation between genotype and phenotype, e.g., Genotypes and Phenotypes (dbGaP) database ( A specific catalogue enabling inquiries on the parent-of-origin effects and imprinting in mice can be found at Databases as well as analytical and graphical tools that specifically enable investigation of new levels of regulation and complexity associated with epigenetic studies will need continuous development and wide availability to facilitate data-mining. Computational methods to manage large genomic data sets are becoming increasingly sophisticated. Such tools can integrate information from various levels of functionality that include DNA sequence, RNA expression, protein isoforms and their post-translational modifications cell, tissue, organ and organismal phenotypes, as well as lifestyle, environmental, dietary and microbial information.

Particularly urgent research needs include development of new technologies to assess epigenetic features in single cells in vitro and in specific cell types in vivo. Surrogate markers in blood cells must also be identified as a way to interrogate cell populations that are generally inaccessible for direct analysis in humans. Finally, technologies are needed to modulate epigenetic changes with greater specificity than genome-wide targeting.


The working group concluded that epigenetics research should incorporate multispecies comparisons to benefit from evolutionary insights and perspectives. Studies will require coordination of multidisciplinary teams combining expertise in clinical and basic research, as well as in computational and modeling methods. New insights and hypotheses will be generated through genomic and epidemiological surveys, including leveraging existing clinical and epidemiological cohorts, experimental animal models and biological materials to test in new experimental and clinical studies. Study designs will need to be based on sufficient statistical power to handle the likely complexity associated with the heterogeneous causes and consequences of epigenetic changes. Phenotyping at a comparable level of rigor, accuracy, and detail as surveys of epigenetic features will be required. Multiple levels of functionality, from cells to the intact organism, should be studied, and the use of several modalities for inducing experimental hypertension in various model systems would help establish general versus context-specific principles. Finally, such endeavors will require the use and continued development of technologies that enable rigorous and quantitative measures of epigenetic and physiological changes.


Sources of Funding: The proceedings of the Epigenetics and Hypertension WG were supported though funds provided by the National Heart Lung and Blood Institute.


Disclosures: None

Useful resources links mentioned in the text

PhysGen Knockout program (“Mechanistic Characterization of Genes for Hypertension and Renal Disease”)

The Knockout Mouse Project (KOMP)

Link Animal Models to Human Disease

Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Genotypes and Phenotypes (dbGaP) database (

Database of parental origin effect on mouse gene imprinting

Contributor Information

Allen W. Cowley, Jr., Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI.

Joseph H. Nadeau, Institute for Systems Biology, Seattle, WA.

Andrea Baccarelli, Laboratory of Environmental Epigenetics, Exposure Epidemiology and Risk Program, Departments of Environmental Health and Epidemiology, Harvard School of Public Health, Boston, MA.

Kathleen Berecek, Department of Physiology & Biophysics, UAB Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL.

Myriam Fornage, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX.

Gary H. Gibbons, Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, GA.

David G. Harrison, Clinical Pharmacology, Vanderbilt School of Medicine, Nashville, TN.

Mingyu Liang, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI.

Peter W. Nathanielsz, Center for Pregnancy and Newborn Research, Dept. OB/GYN, The University of Texas Health Science Center at San Antonio, San Antonio, TX.

Daniel T. O’Connor, Department of Medicine, University of California at San Diego, San Diego, CA.

Jose Ordovas, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA., The Department of Epidemiology and Population Genetics. Centro Nacional Investigación Cardiovasculares (CNIC) Madrid, Spain; and IMDEA Alimentacion, Madrid, Spain.

Weiqun Peng, Department of Physics, The George Washington University, Washington, D.C.

Marcelo Bento Soares, Children’s Memorial Research Center, Falk Brain Tumor Center, Northwestern University, Chicago, IL.

Moshe Szyf, Department of Pharmacology and Therapeutics, McGill University, Montreal Quebec, Canada.

H. Eser Tolunay, Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD.

Katherine C. Wood, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.

Keji Zhao, Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD.

Zorina S. Galis, Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD.


1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217–223. [PubMed]
2. Institute of Medicine (IOM) Report on A Population-Based Policy and Systems Change Approach to Prevent and Control Hypertension. 2010 [PubMed]
3. Wolf-Maier K, Cooper RS, Banegas JR, Giampaoli S, Hense HW, Joffres M, Kastarinen M, Poulter N, Primatesta P, Rodríguez-Artalejo F, Stegmayr B, Thamm M, Tuomilehto J, Vanuzzo D, Vescio F. Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA. 2003;289:2363–2369. [PubMed]
4. Gaziano TA, Bitton A, Anand S, Weinstein MC. The global cost of nonoptimal blood pressure. J Hypertens. 2009;27:1472–1477. [PubMed]
5. Guyton AC. Long-term arterial pressure control: an analysis from animal experiments and computer and graphic models. Am J Physiol. 1990;259:R865–877. [PubMed]
6. Cowley AW., Jr Long-term control of arterial blood pressure. Physiol Rev. 1992;72:231–300. [PubMed]
7. Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001;104:545–556. [PubMed]
8. Saavedra JM. Opportunities and limitations of genetic analysis of hypertensive rat strains. J Hypertens. 2009;27:1129–1133. [PMC free article] [PubMed]
9. Cowley AW., Jr The genetic dissection of essential hypertension. Nat Rev Genet. 2006;7:829–840. [PubMed]
10. Cowley AW, Jr, Roman RJ. The role of the kidney in hypertension. JAMA. 1996;275:1581–1589. [PubMed]
11. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM. Finding the missing heritability of complex diseases. Nature. 2009;461:747–753. [PMC free article] [PubMed]
12. Chakravarti A. Genomics is not enough. Science. 2011;334:15. [PubMed]
13. Altshuler D, Daly MJ, Lander ES. Genetic mapping in human disease. Science. 2008;322:881–888. [PMC free article] [PubMed]
14. Lander ES. Initial impact of the sequencing of the human genome. Nature. 2011;470:187–197. [PubMed]
15. Frazer KA, Murray SS, Schork NJ, Topol EJ. Human genetic variation and its contribution to complex traits. Nat Rev Genet. 2009;10:241–251. [PubMed]
16. Havlik RJ, Garrison RJ, Feinleib M, Kannel WB, Castelli WP, McNamara PM. Blood pressure aggregation in families. Am J Epidemiol. 1979;110:304–312. [PubMed]
17. Levy D, DeStefano AL, Larson MG, O’Donnell CJ, Lifton RP, Gavras H, Cupples LA, Myers RH. Evidence for a blood pressure gene on chromosome 17: genome scan results for longitudinal blood pressure phenotypes in subjects from the Framingham Heart Study. Hypertension. 2000;36:477–483. [PubMed]
18. Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, Glazer NL, Morrison AC, Johnson AD, Aspelund T, Aulchenko Y, Lumley T, Köttgen A, Vasan RS, Rivadeneira F, Eiriksdottir G, Guo X, Arking DE, Mitchell GF, Mattace-Raso FU, Smith AV, Taylor K, Scharpf RB, Hwang SJ, Sijbrands EJ, Bis J, Harris TB, Ganesh SK, O’Donnell CJ, Hofman A, Rotter JI, Coresh J, Benjamin EJ, Uitterlinden AG, Heiss G, Fox CS, Witteman JC, Boerwinkle E, Wang TJ, Gudnason V, Larson MG, Chakravarti A, Psaty BM, van Duijn CM. Genome-wide association study of blood pressure and hypertension. Nat Genet. 2009;41:677–687. [PMC free article] [PubMed]
19. Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, Najjar SS, Zhao JH, Heath SC, Eyheramendy S, Papadakis K, Voight BF, Scott LJ, Zhang F, Farrall M, Tanaka T, Wallace C, Chambers JC, Khaw KT, Nilsson P, van der Harst P, Polidoro S, Grobbee DE, Onland-Moret NC, Bots ML, Wain LV, Elliott KS, Teumer A, Luan J, Lucas G, Kuusisto J, Burton PR, Hadley D, McArdle WL, Brown M, Dominiczak A, Newhouse SJ, Samani NJ, Webster J, Zeggini E, Beckmann JS, Bergmann S, Lim N, Song K, Vollenweider P, Waeber G, Waterworth DM, Yuan X, Groop L, Orho-Melander M, Allione A, Di Gregorio A, Guarrera S, Panico S, Ricceri F, Romanazzi V, Sacerdote C, Vineis P, Barroso I, Sandhu MS, Luben RN, Crawford GJ, Jousilahti P, Perola M, Boehnke M, Bonnycastle LL, Collins FS, Jackson AU, Mohlke KL, Stringham HM, Valle TT, Willer CJ, Bergman RN, Morken MA, Döring A, Gieger C, Illig T, Meitinger T, Org E, Pfeufer A, Wichmann HE, Kathiresan S, Marrugat J, O’Donnell CJ, Schwartz SM, Siscovick DS, Subirana I, Freimer NB, Hartikainen AL, McCarthy MI, O’Reilly PF, Peltonen L, Pouta A, de Jong PE, Snieder H, van Gilst WH, Clarke R, Goel A, Hamsten A, Peden JF, Seedorf U, Syvänen AC, Tognoni G, Lakatta EG, Sanna S, Scheet P, Schlessinger D, Scuteri A, Dörr M, Ernst F, Felix SB, Homuth G, Lorbeer R, Reffelmann T, Rettig R, Völker U, Galan P, Gut IG, Hercberg S, Lathrop GM, Zelenika D, Deloukas P, Soranzo N, Williams FM, Zhai G, Salomaa V, Laakso M, Elosua R, Forouhi NG, Völzke H, Uiterwaal CS, van der Schouw YT, Numans ME, Matullo G, Navis G, Berglund G, Bingham SA, Kooner JS, Connell JM, Bandinelli S, Ferrucci L, Watkins H, Spector TD, Tuomilehto J, Altshuler D, Strachan DP, Laan M, Meneton P, Wareham NJ, Uda M, Jarvelin MR, Mooser V, Melander O, Loos RJ, Elliott P, Abecasis GR, Caulfield M, Munroe PB. Wellcome Trust Case Control Consortium. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet. 2009;41:666–676. [PMC free article] [PubMed]
20. Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, Chasman DI, Smith AV, Tobin MD, Verwoert GC, Hwang SJ, Pihur V, Vollenweider P, O’Reilly PF, Amin N, Bragg-Gresham JL, Teumer A, Glazer NL, Launer L, Zhao JH, Aulchenko Y, Heath S, Sõber S, Parsa A, Luan J, Arora P, Dehghan A, Zhang F, Lucas G, Hicks AA, Jackson AU, Peden JF, Tanaka T, Wild SH, Rudan I, Igl W, Milaneschi Y, Parker AN, Fava C, Chambers JC, Fox ER, Kumari M, Go MJ, van der Harst P, Kao WH, Sjögren M, Vinay DG, Alexander M, Tabara Y, Shaw-Hawkins S, Whincup PH, Liu Y, Shi G, Kuusisto J, Tayo B, Seielstad M, Sim X, Nguyen KD, Lehtimäki T, Matullo G, Wu Y, Gaunt TR, Onland-Moret NC, Cooper MN, Platou CG, Org E, Hardy R, Dahgam S, Palmen J, Vitart V, Braund PS, Kuznetsova T, Uiterwaal CS, Adeyemo A, Palmas W, Campbell H, Ludwig B, Tomaszewski M, Tzoulaki I, Palmer ND, Aspelund T, Garcia M, Chang YP, O’Connell JR, Steinle NI, Grobbee DE, Arking DE, Kardia SL, Morrison AC, Hernandez D, Najjar S, McArdle WL, Hadley D, Brown MJ, Connell JM, Hingorani AD, Day IN, Lawlor DA, Beilby JP, Lawrence RW, Clarke R, Hopewell JC, Ongen H, Dreisbach AW, Li Y, Young JH, Bis JC, Kähönen M, Viikari J, Adair LS, Lee NR, Chen MH, Olden M, Pattaro C, Bolton JA, Köttgen A, Bergmann S, Mooser V, Chaturvedi N, Frayling TM, Islam M, Jafar TH, Erdmann J, Kulkarni SR, Bornstein SR, Grässler J, Groop L, Voight BF, Kettunen J, Howard P, Taylor A, Guarrera S, Ricceri F, Emilsson V, Plump A, Barroso I, Khaw KT, Weder AB, Hunt SC, Sun YV, Bergman RN, Collins FS, Bonnycastle LL, Scott LJ, Stringham HM, Peltonen L, Perola M, Vartiainen E, Brand SM, Staessen JA, Wang TJ, Burton PR, Artigas MS, Dong Y, Snieder H, Wang X, Zhu H, Lohman KK, Rudock ME, Heckbert SR, Smith NL, Wiggins KL, Doumatey A, Shriner D, Veldre G, Viigimaa M, Kinra S, Prabhakaran D, Tripathy V, Langefeld CD, Rosengren A, Thelle DS, Corsi AM, Singleton A, Forrester T, Hilton G, McKenzie CA, Salako T, Iwai N, Kita Y, Ogihara T, Ohkubo T, Okamura T, Ueshima H, Umemura S, Eyheramendy S, Meitinger T, Wichmann HE, Cho YS, Kim HL, Lee JY, Scott J, Sehmi JS, Zhang W, Hedblad B, Nilsson P, Smith GD, Wong A, Narisu N, Stančáková A, Raffel LJ, Yao J, Kathiresan S, O’Donnell CJ, Schwartz SM, Ikram MA, Longstreth WT, Jr, Mosley TH, Seshadri S, Shrine NR, Wain LV, Morken MA, Swift AJ, Laitinen J, Prokopenko I, Zitting P, Cooper JA, Humphries SE, Danesh J, Rasheed A, Goel A, Hamsten A, Watkins H, Bakker SJ, van Gilst WH, Janipalli CS, Mani KR, Yajnik CS, Hofman A, Mattace-Raso FU, Oostra BA, Demirkan A, Isaacs A, Rivadeneira F, Lakatta EG, Orru M, Scuteri A, Ala-Korpela M, Kangas AJ, Lyytikäinen LP, Soininen P, Tukiainen T, Würtz P, Ong RT, Dörr M, Kroemer HK, Völker U, Völzke H, Galan P, Hercberg S, Lathrop M, Zelenika D, Deloukas P, Mangino M, Spector TD, Zhai G, Meschia JF, Nalls MA, Sharma P, Terzic J, Kumar MV, Denniff M, Zukowska-Szczechowska E, Wagenknecht LE, Fowkes FG, Charchar FJ, Schwarz PE, Hayward C, Guo X, Rotimi C, Bots ML, Brand E, Samani NJ, Polasek O, Talmud PJ, Nyberg F, Kuh D, Laan M, Hveem K, Palmer LJ, van der Schouw YT, Casas JP, Mohlke KL, Vineis P, Raitakari O, Ganesh SK, Wong TY, Tai ES, Cooper RS, Laakso M, Rao DC, Harris TB, Morris RW, Dominiczak AF, Kivimaki M, Marmot MG, Miki T, Saleheen D, Chandak GR, Coresh J, Navis G, Salomaa V, Han BG, Zhu X, Kooner JS, Melander O, Ridker PM, Bandinelli S, Gyllensten UB, Wright AF, Wilson JF, Ferrucci L, Farrall M, Tuomilehto J, Pramstaller PP, Elosua R, Soranzo N, Sijbrands EJ, Altshuler D, Loos RJ, Shuldiner AR, Gieger C, Meneton P, Uitterlinden AG, Wareham NJ, Gudnason V, Rotter JI, Rettig R, Uda M, Strachan DP, Witteman JC, Hartikainen AL, Beckmann JS, Boerwinkle E, Vasan RS, Boehnke M, Larson MG, Järvelin MR, Psaty BM, Abecasis GR, Chakravarti A, Elliott P, van Duijn CM, Newton-Cheh C, Levy D, Caulfield MJ, Johnson T, Tang H, Knowles J, Hlatky M, Fortmann S, Assimes TL, Quertermous T, Go A, Iribarren C, Absher D, Risch N, Myers R, Sidney S, Ziegler A, Schillert A, Bickel C, Sinning C, Rupprecht HJ, Lackner K, Wild P, Schnabel R, Blankenberg S, Zeller T, Münzel T, Perret C, Cambien F, Tiret L, Nicaud V, Proust C, Dehghan A, Hofman A, Uitterlinden A, van Duijn C, Levy D, Whitteman J, Cupples LA, Demissie-Banjaw S, Ramachandran V, Smith A, Gudnason V, Boerwinkle E, Folsom A, Morrison A, Psaty BM, Chen IY, Rotter JI, Bis J, Volcik K, Rice K, Taylor KD, Marciante K, Smith N, Glazer N, Heckbert S, Harris T, Lumley T, Kong A, Thorleifsson G, Thorgeirsson G, Holm H, Gulcher JR, Stefansson K, Andersen K, Gretarsdottir S, Thorsteinsdottir U, Preuss M, Schreiber S, Meitinger T, König IR, Lieb W, Hengstenberg C, Schunkert H, Erdmann J, Fischer M, Grosshennig A, Medack A, Stark K, Linsel-Nitschke P, Bruse P, Aherrahrou Z, Peters A, Loley C, Willenborg C, Nahrstedt J, Freyer J, Gulde S, Doering A, Meisinger C, Wichmann HE, Klopp N, Illig T, Meinitzer A, Tomaschitz A, Halperin E, Dobnig H, Scharnagl H, Kleber M, Laaksonen R, Pilz S, Grammer TB, Stojakovic T, Renner W, März W, Böhm BO, Winkelmann BR, Winkler K, Hoffmann MM, O’Donnell CJ, Voight BF, Altshuler D, Siscovick DS, Musunuru K, Peltonen L, Barbalic M, Melander O, Elosua R, Kathiresan S, Schwartz SM, Salomaa V, Guiducci C, Burtt N, Gabriel SB, Stewart AF, Wells GA, Chen L, Jarinova O, Roberts R, McPherson R, Dandona S, Pichard AD, Rader DJ, Devaney J, Lindsay JM, Kent KM, Qu L, Satler L, Burnett MS, Li M, Reilly MP, Wilensky R, Waksman R, Epstein S, Matthai W, Knouff CW, Waterworth DM, Hakonarson HH, Walker MC, Mooser V, Hall AS, Balmforth AJ, Wright BJ, Nelson C, Thompson JR, Samani NJ, Braund PS, Ball SG, Smith NL, Felix JF, Morrison AC, Demissie S, Glazer NL, Loehr LR, Cupples LA, Dehghan A, Lumley T, Rosamond WD, Lieb W, Rivadeneira F, Bis JC, Folsom AR, Benjamin E, Aulchenko YS, Haritunians T, Couper D, Murabito J, Wang YA, Stricker BH, Gottdiener JS, Chang PP, Wang TJ, Rice KM, Hofman A, Heckbert SR, Fox ER, O’Donnell CJ, Uitterlinden AG, Rotter JI, Willerson JT, Levy D, van Duijn CM, Psaty BM, Witteman JC, Boerwinkle E, Vasan RS, Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Glazer NL, Parsa A, Gao X, Yang Q, Smith AV, O’Connell JR, Li M, Schmidt H, Tanaka T, Isaacs A, Ketkar S, Hwang SJ, Johnson AD, Dehghan A, Teumer A, Paré G, Atkinson EJ, Zeller T, Lohman K, Cornelis MC, Probst-Hensch NM, Kronenberg F, Tönjes A, Hayward C, Aspelund T, Eiriksdottir G, Launer LJ, Harris TB, Rampersaud E, Mitchell BD, Arking DE, Boerwinkle E, Struchalin M, Cavalieri M, Singleton A, Giallauria F, Metter J, de Boer J, Haritunians T, Lumley T, Siscovick D, Psaty BM, Zillikens MC, Oostra BA, Feitosa M, Province M, de Andrade M, Turner ST, Schillert A, Ziegler A, Wild PS, Schnabel RB, Wilde S, Munzel TF, Leak TS, Illig T, Klopp N, Meisinger C, Wichmann HE, Koenig W, Zgaga L, Zemunik T, Kolcic I, Minelli C, Hu FB, Johansson A, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Schreiber S, Aulchenko YS, Felix JF, Rivadeneira F, Uitterlinden AG, Hofman A, Imboden M, Nitsch D, Brandstätter A, Kollerits B, Kedenko L, Mägi R, Stumvoll M, Kovacs P, Boban M, Campbell S, Endlich K, Völzke H, Kroemer HK, Nauck M, Völker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Blankenberg S, Liu Y, Curhan GC, Franke A, Rochat T, Paulweber B, Prokopenko I, Wang W, Gudnason V, Shuldiner AR, Coresh J, Schmidt R, Ferrucci L, Shlipak MG, van Duijn CM, Borecki I, Krämer BK, Rudan I, Gyllensten U, Wilson JF, Witteman JC, Pramstaller PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS, Vasan RS, Glazer NL, Felix JF, Lieb W, Wild PS, Felix SB, Watzinger N, Larson MG, Smith NL, Dehghan A, Grosshennig A, Schillert A, Teumer A, Schmidt R, Kathiresan S, Lumley T, Aulchenko YS, König IR, Zeller T, Homuth G, Struchalin M, Aragam J, Bis JC, Rivadeneira F, Erdmann J, Schnabel RB, Dörr M, Zweiker R, Lind L, Rodeheffer RJ, Greiser KH, Levy D, Haritunians T, Deckers JW, Stritzke J, Lackner KJ, Völker U, Ingelsson E, Kullo I, Haerting J, O’Donnell CJ, Heckbert SR, Stricker BH, Ziegler A, Reffelmann T, Redfield MM, Werdan K, Mitchell GF, Rice K, Arnett DK, Hofman A, Gottdiener JS, Uitterlinden AG, Meitinger T, Blettner M, Friedrich N, Wang TJ, Psaty BM, van Duijn CM, Wichmann HE, Munzel TF, Kroemer HK, Benjamin EJ, Rotter JI, Witteman JC, Schunkert H, Schmidt H, Völzke H, Blankenberg S, Chambers JC, Zhang W, Lord GM, van der Harst P, Lawlor DA, Sehmi JS, Gale DP, Wass MN, Ahmadi KR, Bakker SJ, Beckmann J, Bilo HJ, Bochud M, Brown MJ, Caulfield MJ, Connell JM, Cook HT, Cotlarciuc I, Davey Smith G, de Silva R, Deng G, Devuyst O, Dikkeschei LD, Dimkovic N, Dockrell M, Dominiczak A, Ebrahim S, Eggermann T, Farrall M, Ferrucci L, Floege J, Forouhi NG, Gansevoort RT, Han X, Hedblad B, Homan van der Heide JJ, Hepkema BG, Hernandez-Fuentes M, Hypponen E, Johnson T, de Jong PE, Kleefstra N, Lagou V, Lapsley M, Li Y, Loos RJ, Luan J, Luttropp K, Maréchal C, Melander O, Munroe PB, Nordfors L, Parsa A, Peltonen L, Penninx BW, Perucha E, Pouta A, Prokopenko I, Roderick PJ, Ruokonen A, Samani NJ, Sanna S, Schalling M, Schlessinger D, Schlieper G, Seelen MA, Shuldiner AR, Sjögren M, Smit JH, Snieder H, Soranzo N, Spector TD, Stenvinkel P, Sternberg MJ, Swaminathan R, Tanaka T, Ubink-Veltmaat LJ, Uda M, Vollenweider P, Wallace C, Waterworth D, Zerres K, Waeber G, Wareham NJ, Maxwell PH, McCarthy MI, Jarvelin MR, Mooser V, Abecasis GR, Lightstone L, Scott J, Navis G, Elliott P, Kooner JS. CARDIoGRAM consortium; CKDGen Consortium; KidneyGen Consortium; EchoGen consortium; CHARGE-HF consortium. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011;478:103–109. [PMC free article] [PubMed]
21. Wang Y, O’Connell JR, McArdle PF, Wade JB, Dorff SE, Shah SJ, Shi X, Pan L, Rampersaud E, Shen H, Kim JD, Subramanya AR, Steinle NI, Parsa A, Ober CC, Welling PA, Chakravarti A, Weder AB, Cooper RS, Mitchell BD, Shuldiner AR, Chang YP. Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci USA. 2009;106:226–231. [PubMed]
22. Hirschhorn JN. Genetic approaches to studying common diseases and complex traits. Pediatr Res. 2005;57:74R–77R. [PubMed]
23. Shao H, Burrage LC, Sinasac DS, Hill AE, Ernest SR, O’Brien W, Courtland HW, Jepsen KJ, Kirby A, Kulbokas EJ, Daly MJ, Broman KW, Lander ES, Nadeau JH. Genetic architecture of complex traits: large phenotypic effects and pervasive epistasis. Proc Natl Acad Sci USA. 2008;105:19910–19914. [PubMed]
24. Zuk O, Hechter E, Sunyaev SR, Lander ES. The mystery of missing heritability: Genetic interactions create phantom heritability. Proc Natl Acad Sci USA. 2012;109:1193–1198. [PubMed]
25. Waddington CH. The Strategy of the Genes. George Allen and Unwin Ltd.; London: 1957.
26. Branco MR, Ficz G, Reik W. Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat Rev Genet. 2011;13:7–13. [PubMed]
27. Nadeau JH. Transgenerational genetic effects on phenotypic variation and disease risk. Hum Mol Genet. 2009;18:R202–210. [PMC free article] [PubMed]
28. Nelson VR, Nadeau JH. Transgenerational genetic effects. Epigenomics. 2010;2:797–806. [PMC free article] [PubMed]
29. Guerrero-Bosagna C, Skinner MK. Environmentally induced epigenetic transgenerational inheritance of phenotype and disease. Mol Cell Endocrinol. 2011 In Press. [PMC free article] [PubMed]
30. Youngson NA, Whitelaw E. Transgenerational epigenetic effects. Annu Rev Genomics Hum Genet. 2008;9:233–257. [PubMed]
31. Ferguson-Smith AC. Genomic imprinting: the emergence of an epigenetic paradigm. Nat Rev Genet. 2011;12:565–575. [PubMed]
32. Millis RM. Epigenetics and hypertension. Curr Hypertens Rep. 2011;13:21–28. [PubMed]
33. Baylin SB, Jones PA. A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer. 2011;11:726–734. [PMC free article] [PubMed]
34. Baccarelli A, Rienstra M, Benjamin EJ. Cardiovascular epigenetics: basic concepts and results from animal and human studies. Circ Cardiovasc Genet. 2010;3:567–573. [PMC free article] [PubMed]
35. Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature. 2010;467:963–966. [PubMed]
36. Yazbek SN, Spiezio SH, Nadeau JH, Buchner DA. Ancestral paternal genotype controls body weight and food intake for multiple generations. Hum Mol Genet. 2010;19:4134–4144. [PMC free article] [PubMed]
37. Greer EL, Maures TJ, Ucar D, Hauswirth AG, Mancini E, Lim JP, Benayoun BA, Shi Y, Brunet A. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature. 2011;479:365–371. [PMC free article] [PubMed]
38. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA. 2005;102:10604–10609. [PubMed]
39. Szyf M. The early life social environment and DNA methylation: DNA methylation mediating the long-term impact of social environments early in life. Epigenetics. 2011;6:971–978. [PMC free article] [PubMed]
40. Gluckman PD, Hanson MA, Beedle AS. Non-genomic transgenerational inheritance of disease risk. Bioessays. 2007;29:145–154. [PubMed]
41. Gluckman PD, Hanson MA, Buklijas T, Low FM, Beedle AS. Epigenetic mechanismsthat underpin metabolic and cardiovascular diseases. Nat Rev Endocrinol. 2009;5:401–408. [PubMed]
42. Low FM, Gluckman PD, Hanson MA. Developmental plasticity and epigenetic mechanisms underpinning metabolic and cardiovascular diseases. Epigenomics. 2011;3:279–294. [PubMed]
43. Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003;23:5293–5300. [PMC free article] [PubMed]
44. Schier AF. The maternal-zygotic transition: death and birth of RNAs. Science. 2007;316:406–407. [PubMed]
45. Xing Y, Shi S, Le L, Lee CA, Silver-Morse L, Li WX. Evidence for transgenerational transmission of epigenetic tumor susceptibility in Drosophila. PLoS Genet. 2007;3:1598–1606. [PubMed]
46. Lam MY, Heaney JD, Youngren KK, Kawasoe JH, Nadeau JH. Trans-generational epistasis between Dnd1Ter and other modifier genes controls susceptibility to testicular germ cell tumors. Hum Mol Genet. 2007;16:2233–2240. [PubMed]
47. Yazbek SN, Buchner DA, Geisinger JM, Burrage LC, Spiezio SH, Zentner GE, Hsieh CW, Scacheri PC, Croniger CM, Nadeau JH. Deep congenic analysis identifies many strong, context-dependent QTLs, one of which, Slc35b4, regulates obesity and glucose homeostasis. Genome Res. 2011;21:1065–1073. [PubMed]
48. Cuzin F, Rassoulzadegan M. Non-Mendelian epigenetic heredity: gametic RNAs as epigenetic regulators and transgenerational signals. Essays Biochem. 2010;48:101–106. [PubMed]
49. Bateson P. Fetal experience and good adult design. Int J Epidemiol. 2001;30:928–934. [PubMed]
50. Gluckman PD, Hanson MA. Living with the past: evolution, development, and patterns of disease. Science. 2004;305:1733–1736. [PubMed]
51. Bateson P, Barker D, Clutton-Brock T, Deb D, D’Udine B, Foley RA, Gluckman P, Godfrey K, Kirkwood T, Lahr MM, McNamara J, Metcalfe NB, Monaghan P, Spencer HG, Sultan SE. Developmental plasticity and human health. Nature. 2004;430:419–421. [PubMed]
52. Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ. Epigenetic programming by maternal behavior. Nat Neurosci. 2004;7:847–854. [PubMed]
53. Molaro A, Hodges E, Fang F, Song Q, McCombie WR, Hannon GJ, Smith AD. Sperm methylation profiles reveal features of epigenetic inheritance and evolution in primates. Cell. 2011;146:1029–1041. [PMC free article] [PubMed]
54. Gervin K, Vigeland MD, Mattingsdal M, Hammer M, Nygaord H, Olsen AO, Brandt I, Harris JR, Undlien DE, Lyle R. DNA methylation and gene expression changes in monzygotic twins discordant for psoriasis: identification of epigenetically dysregulated genes. PLoS Genetics. 2012;8:e1002454. [PMC free article] [PubMed]