Review

Genetic basis of blood pressure and

hypertension
Sandosh Padmanabhan1, Christopher Newton-Cheh2 and Anna F. Dominiczak1
1

Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow,
Glasgow G12 8TA, UK
2
Harvard Medical School, Massachusetts General Hospital, Broad Institute of Harvard University and Massachusetts Institute
of Technology, Boston, MA 02114, USA

Blood pressure (BP) is a complex trait regulated by an

intricate network of physiological pathways involving
extracellular fluid volume homeostasis, cardiac contractility and vascular tone through renal, neural or endocrine
systems. Untreated high BP, or hypertension (HTN), is
associated with increased mortality, and thus a better
understanding of the pathophysiological and genetic
underpinnings of BP regulation will have a major impact
on public health. However, identifying genes that contribute to BP and HTN has proved challenging. In this review
we describe our current understanding of the genetic
architecture of BP and HTN, which has accelerated over
the past five years primarily owing to genome-wide association studies (GWAS) and the continuing progress in
uncovering rare gene mutations, epigenetic markers and
regulatory pathways involved in the physiology of BP. We
also look ahead to future studies characterizing novel
pathways that affect BP and HTN and discuss strategies
for translating current findings to the clinic.
The complexity of BP and HTN
BP is a quantitative trait that is distributed normally in
the general population. In adults there is a continuous,
incremental risk of cardiovascular disease, stroke and
renal disease associated with high BP. HTN is defined
based on a cut-off at the upper end of the distribution of BP
at which the benefits of action (i.e., therapeutic intervention) exceed those of inaction [1]. Based on this definition,
there are over 1 billion people with HTN worldwide, and
the World Health Organization suggests this will rise to
1.5 billion by 2020 [2]. The high prevalence of HTN and its
consequent significant adverse economic impact on the
individual and population highlight the importance of
primary prevention of HTN. Thus, there is a pressing
need for a greater understanding of the pathophysiological
and genetic underpinnings of BP regulation and dysregulation. Studies have demonstrated that BP is a genetically
determined trait, with estimates of heritability ranging
from 31% to 68% [3,4]. The BP/HTN phenotype poses
unique challenges for genetic dissection that have made
progress slow (Box 1). BP levels are determined by cardiac
output and peripheral vascular resistance, and these in
turn are regulated by a complex network of interacting
physiological pathways involving extracellular fluid
Corresponding author: Dominiczak, A.F. (Anna.Dominiczak@glasgow.ac.uk).
Keywords: hypertension; blood pressure; genetics; sodium; artery; kidney.

volume homeostasis, cardiac contractility and vascular

tone through renal, neural or endocrine systems. Perturbations in any of these physiological pathways can arise
from environmental (for example salt intake) or genetic
factors or a combination of both that result in high or low
BP. Rare monogenic BP syndromes are characterized by a
major gene defect affecting a single pathway commonly
involving renal electrolyte balance (Box 2). The phenotypic heterogeneity is further complicated by intra-individual
BP variability caused by a large number of factors including measurement technique, instrument error and patient
factors such as anxiety and activity level [5]. All these
genotypic and phenotypic complexities have resulted in
both false-positive and false-negative studies in the past.
The search for BP genes initially focused on genome-wide
linkage studies that were successful in uncovering genes
for monogenic forms of high and low blood pressure but
turned out to be largely unsuccessful in explaining the
polygenic BP phenotype. The recent successes of GWAS
[612] are testament to greater rigor in phenotypic characterization and statistical design. The limitations and
potential of GWAS in the dissection of hypertension are
highlighted in a recent debate [13,14].
In this review we describe the explosion in our understanding of the genetic architecture of BP and HTN that
has occurred over the past five years and the continuing
progress in uncovering new gene mutations causing rare
inherited forms of HTN and hypotension. We review the
road ahead, highlighting the novel pathways identified,
both common and rare, and discuss future strategies to
uncover novel mechanisms and clinical translation. Table
1 summarizes the genomic and functional context of all the
monogenic and GWAS BP/HTN loci discovered to date.
Common variants
GWAS use dense sets of single nucleotide polymorphisms
(SNPs; usually 500 0001 000 000) and rely on linkage
disequilibrium (LD) or correlation patterns of typed (or
imputed) SNPs with functional variants. This means the
identified SNPs are usually proxies of ungenotyped functional variants. Although these SNPs show unequivocal
association with BP, the functional dissection of these
signals is not straightforward. Associations detected by
GWAS between BP/HTN and SNPs, with 50 kb flanking
segments, are shown in Figure 1 (GWAS SNPs were selected from studies with sample sizes greater than 20 000

0168-9525/$ see front matter 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tig.2012.04.001 Trends in Genetics, August 2012, Vol. 28, No. 8

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Box 1. Phenotypic complexity

Variation in extracellular fluid volume, the contractile state of the heart
and vascular tone contribute to variation in BP level. Other determinants of BP include age, weight, ethnicity and diet. Systolic BP (SBP)
increases linearly from age 30 to 84 years together with mean arterial
pressure [a weighted average of SBP and diastolic pressure (DBP)],
but DBP increases linearly up to age 5060, after which it begins to
decline with a steep increase in pulse pressure (the difference between
SBP and DBP) [52,53]. The late decline of DBP after age 60 and the
continuous rise in systolic BP reflects the increased large artery
stiffness in older age. The odds of progression to HTN increase by 20
30% for every 5% gain in body weight.
At all ages, HTN is more common in African Americans than in
whites; in all ethnic and racial groups it is more common in those with
lower socioeconomic status. Interestingly, HTN is more prevalent in

and SNPs attaining a P value <5108 for significant

association). Many of the SNPs from GWAS that attained
genome-wide significance also show similar strong associations for other traits (pleiotropy) (Figure 1a) for example,
rs13333226 shows independent association with HTN and
chronic kidney disease [11,15,16]; rs3184504 shows

the African-American population in the USA than in either AfroCaribbean or native black African populations [5456]. In some
societies, BP shows only a small age-related increase and may be
related in part to their agrarian lifestyle as well as the high potassium,
low sodium diet of the hunter-gatherer, a more rural lifestyle and a
lower consumption of food [5760]. From an evolutionary perspective,
essential HTN is a disease of civilization with its abundance of
processed foods and long lifespans and could be an undesirable
pleiotropic effect of a genotype that may have optimized fitness in an
ancient environment [61]. The rates of HTN and sodium sensitivity are
generally higher in individuals carrying the ancestral alleles of
sodium-conserving genes, which show strong latitudinal clines with
the ancestral sodium-conserving alleles more prevalent in African
populations and less so in the northern regions [6264].

significant association with chronic kidney disease, celiac

disease, type 1 diabetes, coronary artery disease, cholesterol, hemoglobin, retinal vascular caliber, plasma eosinophil count and rheumatoid arthritis [6,9,1624]; rs1799945
is also associated with serum iron concentration and
hemoglobin levels in addition to its association with blood

Box 2. Qualitative or quantitative phenotype

(b)

Hypertension

Population frequency

Platt

Pickering

Population frequency

(a)

Platt, hypertensive individuals were a distinct sub-population,

whereas according to Pickering, hypertension was only the upper
portion of a continuous distribution curve of BP. The debate dragged
on through the 1960s with much resistance to accepting Pickerings
quantitative model; this only changed with mounting evidence from
epidemiological studies indicating that high BP was a risk factor for
cardiovascular disease and intervention trials of antihypertensive
therapy all showing similar benefits of reducing BP. Further support
comes from large-scale GWAS for BP that have mapped common
variants at 29 loci with small effects [6,811,67]. However, Platts
model cannot be discounted entirely because there are rare
mendelian forms of HTN and hypotension that are caused by highly
penetrant rare genetic variants with large effects [40]. Pickerings
concession at the end of the long debate aptly summarizes the current
understanding of HTN genetics I never denied the possibility that
there may be a group in what we now call essential hypertension
characterized by single-gene inheritance.

Hypertension

From a genetic perspective, whether BP is considered as a

quantitative trait or a dichotomous disease phenotype has major
implications for studies of genetic causation, and this was recognized
very early. In the 1950s a technical controversy about the unimodal or
bimodal distribution of blood pressure led to the famous Platt
Pickering debate [65], and this is a useful platform to understand the
assumptions that have driven genetic research of BP/HTN so far
(Figure I). Platt measured BP in normotensive and hypertensive
probands and their relatives and found a bimodal distribution of BP
values (Figure Ia). This led him to argue that HTN was simple
mendelian disease caused by a single dominant genetic mutation. By
contrast, Pickering studied BP distributions from the second to eighth
decades in first-degree relatives of normotensive and hypertensive
probands and instead found a unimodal distribution of BP (Figure Ib).
Pickering concluded that the continuous Gaussian distribution of BP
values indicated that BP was inherited as a graded character and is
hence a polygenic non-mendelian trait [65,66]. Thus, according to

Gene (0-n)
Gene mutation absent

Blood pressure

Gene mutation present

Environment (0-n)

Blood pressure
TRENDS in Genetics

Figure I. The PlattPickering debate about the quantitative or qualitative nature of HTN. (a) Platt argued that HTN occurred in a discrete subpopulation and was caused
by a single, heritable genetic mutation. (b) Pickering suggested that there was a range of BP levels in the population, and that there was no clear dividing line between
hypertension and normotension; instead, HTN represented the end of a continuum and was therefore polygenic in origin.

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Table 1. Genetic loci associated with monogenic BP syndromes and identified through GWASa
CHR

GWAS b

Monogenic syndrome

1p36.13

Gene/nearest
gene
CLCNKB

1p36.13

SDHB

1p36.2

MTHFR
(NPPA, NPPB)

1q23.3

SDHC

1q42.2

AGT

2q36.2

CUL3

3p25.3

VHL

3q22.1

ULK4

CHARGE, GBPG, ICBP

3q26.2

GBPG, ICBP

4q21.2

MECOM
(MDS1)
FGF5

4q31.2

NR3C2

5p15.3

SDHA

5p13.3

NPR3

5q31.2

KLHL3

6p22.2

HFE

7p22

Pathway

Notes

Bartter syndrome, type 3

OMIM #607364

Renal electrolyte
balance

Paragangliomas 4
OMIM #115310

Sympathetic system

Autosomal recessive
Impaired chloride reabsorption in
the thick ascending loop of Henle
leads to impaired sodium
reabsorption
Low/normal BP
Multiple catecholamine-secreting
head and neck paragangliomas and
retroperitoneal
pheochromocytomas
Methylene-tetrahydrofolate
reductase; has been associated
with changes in plasma
homocysteine levels and preeclampsia. Atrial natriuretic and
brain natriuretic peptides genes
have been associated with
hypertension
Tumors or extra-adrenal
paraganglia- associated
pheochromocytoma
The cleaved products angiotensin I,
angiotensin II and angiotensin III
are known regulators of BP and
sodium homeostasis
Modulation of renal salt, K+ and H+
handling in response to
physiological challenge
Autosomal dominant
Associated with retinal, cerebellar,
and spinal hemangioblastoma,
renal cell carcinoma (RCC),
pheochromocytoma, and
pancreatic tumors
Serine-threonine kinase of
unknown function
Myelodysplasia syndrome
protein 1
Fibroblast growth factor 5;
stimulates cell growth and
proliferation and is associated with
angiogenesis
Autosomal dominant
Missense mutation (S810L) in the
mineralocorticoid receptor
Low-renin, low-aldosterone,
hypokalemia

CHARGE, GBPG,
AGEN, ICBP,
Gene-centric

Paragangliomas 3
OMIM #605373

Renal electrolyte
balance

Sympathetic system

Gene-centric

Pseudohypoaldosteronism
type IIE
OMIM *603136
von HippelLindau syndrome
OMIM #193300

Renal electrolyte
balance,
vascular function
Renal electrolyte
balance
Sympathetic system

GBPG, AGEN, ICBP

Hypertension exacerbation
in pregnancy
OMIM #605115

Renal electrolyte
balance

Pseudohypoaldosteronism
type I
OMIM #177735

Renal electrolyte
balance

Autosomal dominant
Renal unresponsiveness to
mineralocorticoids

Paragangliomas 5
OMIM #614165

Sympathetic system

Tumors or extra-adrenal
paraganglia-associated
pheochromocytoma
Natriuretic peptide clearance
receptor
Modulation of renal salt, K+ and H+
handling in response to
physiological challenge
Autosomal recessive
Iron metabolism
Autosomal dominant
Hyperaldosteronism due to
adrenocortical hyperplasia not
suppressed by dexamethasone

AGEN, ICBP,
Gene-centric
Pseudohypoaldosteronism
type IID
OMIM #614495
Hemochromatosis
OMIM #235200
Familial
hyperaldosteronism type 2
OMIM #605635

Renal electrolyte
balance
Renal electrolyte
balance

ICBP, Gene-centric
Steroid/aldosterone
synthesis

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Table 1 (Continued )
Gene/nearest
gene
NOS3

Monogenic syndrome

GWAS b

Pathway

Notes

Pregnancy-induced
hypertension
OMIM +163729

HYPERGENES,
Gene-centric

Endothelial function

8q24.3

CYP11B1,
CYP11B2

8q24.3

CYP11B2

8q24.3

CYP11B1

Familial
hyperaldosteronism type 1
Glucocorticoidremediable
aldosteronism (GRA)
OMIM #103900
Corticosterone
methyloxidase
II deficiency
OMIM #61060
Steroid 11b-hydroxylase
deficiency
OMIM #202010

10p12.3

CACNB2

10q11.2

RET

Multiple endocrine
neoplasia type IIA
OMIM #171400

10q24.3

CYP17A1

17a-hydroxylase and/or
17,20-lyase deficiency
OMIM *609300

11p15.1

PLEKHA7

CHARGE, ICBP

11p15.2

SOX6

Gene-centric

Transcription

11p15.5

LSP1/TNNT3

Gene-centric

?Endothelial
function

11q12.2

SDHAF2

Paragangliomas 2
OMIM #601650

Sympathetic
system

11q23.1

SDHD

Paragangliomas 1
OMIM #16800

Sympathetic
system

11q24.3

KCNJ1

Bartter syndrome,
antenatal, type 2
OMIM #241200
Hypertension with
Brachydactyly
Bilginturan syndrome
OMIM %112410
Pseudohypoaldosteronism
type IIC
Gordons syndrome
OMIM #614492

Renal electrolyte
balance

Nitric oxide plays an important role

in the maintenance of
cardiovascular and renal
homeostasis
Autosomal dominant
Chimeric gene
Plasma and urinary aldosterone
responsive to ACTH;
dexamethasone suppressible
within 48 h
Autosomal recessive
Enzymatic defect results in
decreased aldosterone and saltwasting
Enzyme dysfunction leads to
increased levels of MR-activating
hormones
Subunit of voltage-gated calcium
channel expressed in heart
Autosomal dominant
Associated with multiple endocrine
neoplasms, including medullary
thyroid carcinoma,
pheochromocytoma, and
parathyroid adenomas
Cytochrome p450 enzyme
mediating the first step in
mineralocorticoid and
glucocorticoid synthesis. Enzyme
dysfunction leads to increased
levels of MR activating hormones.
Also involved in sex steroid
synthesis
Plextrin-homology domaincontaining family member
expressed in zona adherens of
epithelial cells
Required for normal development
of the central nervous system,
chondrogenesis, and maintenance
of cardiac and skeletal muscle cells
Expressed in leukocytes and
endothelial cells. Involved in
signaling, regulating the
cytoskeletal architecture and
neutrophil migration
Tumors or extra-adrenal
paraganglia-associated
pheochromocytoma
Tumors or extra-adrenal
paraganglia associated
pheochromocytoma
Reduced potassium recycling leads
to impaired sodium
Reabsorption
Inversion, deletion, and reinsertion
at 12p12.2 to p11.2
No specific biochemical findings

CHR
7q36.1

12p12.2

12p12.3

WNK1

12q21.3

ATP2B1

400

Steroid/aldosterone
synthesis

Steroid/aldosterone
synthesis

Steroid/aldosterone
synthesis
CHARGE, ICBP

?Vascular/cardiac
function
Sympathetic
system

CHARGE, GBPG,
AGEN-BP, ICBP

Steroid/aldosterone
synthesis

Renal electrolyte
balance

CHARGE, GBPG, AGEN,

ICBP, Gene-centric

?Vascular function

Autosomal dominant
Gain-of-function mutations in
WNK1
Low plasma renin, normal or
elevated K+
Encodes plasma membrane
calcium- or calmodulin-dependent
ATPase expressed in endothelium

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Table 1 (Continued )
CHR

Monogenic syndrome

GWAS b

Pathway

Notes

CHARGE, GBPG, ICBP

?Endothelial
function

Also known as lymphocyte-specific

adaptor protein (LNK), may
regulate hematopoietic progenitors
and inflammatory signaling
pathways in endothelium
T-box genes involved in regulation
of developmental processes
Homozygous or compound
heterozygous mutation in the
sodium-potassium-chloride
cotransporter-2 gene
Cytoplasmic tyrosine kinase
involved in angiotensin IIdependent vascular smooth muscle
cell contraction
Autosomal dominant
Constitutive activation of epithelial
sodium
transporter, ENaC. Low plasma
renin, low or normal K+; negligible
urinary aldosterone
Uromodulin; TammHorsfall
protein. Specifically expressed in
the thick ascending limb of the loop
of Henle where 25% of sodium
reabsorption in the kidney occurs
Low BP
Loss-of-function mutation leads to
lower sodium reabsorption
Autosomal recessive
Increased plasma ACTH and
secretory rates of all corticosteroids
Zinc-finger protein 652
Autosomal dominant
Loss-of-function mutations in
WNK4
Low plasma renin, normal or
elevated K+
GNAS encodes the a subunit of the
G protein mediating b-receptor
signal transduction
EDN3 encodes endothelin 3, the
precursor for the ligand of the
endothelin B receptor

12q24.1

Gene/nearest
gene
SH2B3

12q24.2

TBX5TBX3

15q21.1

SLC12A1

15q24.1

CSK

16p12.2

SCNN1B,
SCNN1G

16p12.3

UMOD

16q13

SLC12A3

Gitelman syndrome
OMIM #263800

Renal electrolyte
balance

16q22.1

HSD11B2

Apparent mineralocorticoid
excess
OMIM # 218030

Steroid/aldosterone
synthesis

17q21.3
17q21.3

ZNF652
WNK4

20q13

GNASEDN3

CHARGE, ICBP
Bartter syndrome,
antenatal, type 1
OMIM #601678

Renal electrolyte
balance

CHARGE, GBPG,
AGEN-BP, ICBP

Liddle syndrome
OMIM #177200

Vascular function

Renal electrolyte
balance

BP-Extremes

?Renal electrolyte
balance
?Renal function

GBPG, AGEN-BP, ICBP

Renal electrolyte
balance

Pseudohypoaldosteronism
type IIB
Gordons syndrome
OMIM #614491
GBPG, ICBP

Vascular function

The key genes at each locus are shown with their known or potential role in BP regulation. The grey shaded rows indicate genes implicated in monogenic syndromes of
high/low BP. The Pathway column is color-coded according to the pathway involved.

GWAS studies: AGEN [7], BP-Extremes [10], CHARGE [8], GBPG [9], Gene-centric [6], HYPERGENES [11], and ICBP [5].

pressure [6,25,26]; and proxies for rs1004467 show genome-wide significant associations with coronary artery
disease, schizophrenia, intracranial aneurysm and parkinsonism [6,810,24,2730]. This illustrates the challenges ahead when attempting to design studies to
functionally dissect these signals. Figure 1a also shows
genes that are associated with monogenic syndromes
from Online Mendelian Inheritance in Man (OMIM) that
occur in the GWAS-related DNA segments shown. The
only genes known to be associated with monogenic forms
of high blood pressure and have been identified by GWAS
are cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1) and nitric oxide synthase 3 (NOS3).
Even once a SNP has been identified that is associated
with HTN, it is difficult to identify the gene involved. For
example, Figure 1b shows the genes within 50 kb on

either side of a blood pressure GWAS SNP, and among

these only a few genes (NPPA, NOS3 and UMOD) have
been clearly linked to the GWAS SNP [11,12,31]. Furthermore, 50 kb is by no means the limit of the zone of
influence of a SNP because the risk-genes implicated by
the GWAS SNPs may lie within the region of linkage
disequilibrium around the SNP, or even more distantly
because SNPs can influence the regulation of remote
genes. GWAS loci are often rich in copy-number variants,
insertion/deletion variants (Figure 1b), microRNA targets and transcription factor binding sites (Figure 1c)
that may influence the genotypephenotype association
and offer another avenue for molecular and functional
experiments to elucidate the causal pathways or more
simply to identify which risk-gene the GWAS SNP
implicates.
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(a)

(b)

TRENDS in Genetics

Figure 1. Phenotypic, genetic and regulatory context of GWAS signals for blood pressure and hypertension. (a) Phenotypic landscape of GWAS signals in BP/HTN GWAS.
The strongest SNPs for BP and HTN also show very little overlap with genes involved in monogenic BP syndromes. Only CYP17A1 and NOS3 are associated with
monogenic BP syndromes and occur within 50 kb of BP GWAS SNPs. The strongest BP GWAS SNPs and their proxies are not associated exclusively with BP phenotypes

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(c)

TRENDS in Genetics

Figure 1. (Continued ).

Finally, the collective effect of all BP loci identified

through GWAS explains only a small fraction (2%) of
BP heritability. Thus, similarly to other common traits, BP
shares the same missing heritability conundrum [32], and
efforts are now directed toward identifying additional
common variants of small effect and rare variants of
greater effect. Although GWAS use SNPs selected to provide genome-wide coverage, they provide limited coverage
of genes with plausible biological relevance (candidate
genes) particularly in relation to lower-frequency genetic
variants (such as those with minor allele frequencies

of 15%). Large-scale gene-centric analysis of BP using a

customized gene array enriched with common, low-frequency variants in 2100 candidate cardiovascular genes
reflecting a wide variety of biological pathways in over
80 000 individuals identified NPR3, HFE, NOS3, SOX6,
LSP1/TNNT3, MTHFR, AGT and ATP2B1, with some
overlap with large GWAS meta-analyses [7]. Among the
single candidate genes studied, NPPA-NPPB [31] and
SCNN1G [33] showed evidence of association with replication, but only the former showed strong concordant signals
in GWAS.

but show pleiotropy with non-BP traits that can either point to plausible underlying pathways (for example UMOD and its association with HTN and kidney function) or
novel common pathways or may be independent associations. The rings from outer to inner represent: (1) chromosomal segments with GWAS SNPs (including 50 kb
flanking region); (2) GWAS SNPs; (3) black markers on chromosomal segments SNP proxy locations for the index SNP in the region (r2>0.8); (4) genes implicated in
monogenic syndromes from OMIM present in the chromosomal regions; (5) non-BP phenotypes that showed genome-wide significance within these loci. (b) Genetic
landscape of GWAS signals in BP/HTN GWAS. Only a few genes (NPPA, NOS3, UMOD) have been clearly linked to the strongest GWAS SNP, whereas many of the SNPs lie
in gene-rich regions, highlighting the challenges ahead in fine-mapping and identifying the causative gene/variant. It is very likely that GWAS SNPs may influence the
regulation of distant genes outside the 50 kb regions shown in this figure. Furthermore, the GWAS loci are also rich in copy-number variants and insertion/deletion variants
that will need to be considered in the functional dissection of GWAS signals. The rings from outer to inner represent 15 as in (a); (6) shows structural variations present
within the chromosomal regions. (c) Regulatory landscape of GWAS signals in BP/HTN GWAS. Bioinformatic analysis of GWAS BP SNP loci show microRNA targets,
conserved transcription factor binding sites, and epigenetic loci, that may influence the genotypephenotype association and offer another avenue for the design of
molecular and functional experiments to elucidate the causal pathways. The SNP positions are indicated by red bars on the chromosome and are the same SNPs as shown
in (a) and (b). The rings from outer to inner represent: (1) MicroRNA targets and associated genes; (2) chromosomal segments with GWAS SNPs (including 50 kb flanking
region); (3) transcription factors binding sites conserved in the human/mouse/rat alignment in the chromosomal regions using TFBS Conserved (tfbsConsSites) in UCSC
Browser showing those transcription factors with score >800; (4) DNase hypersensitive areas assayed in a large collection of cell types; (5) predicted CpG islands. The
height of the line indicates the length of the segment; (ac) were generated using Circos [68] with the Feb 2009(GRCh37/hg19) assembly data from UCSC Genome Browser
(http://genome.ucsc.edu/) [69].

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One striking result of the BP GWAS is that the genes
from highly plausible pathways are not represented near
the identified SNPs (Figure 1). Using the GRAIL textmining algorithm (Gene Relationships Across Implicated
Loci [34]) to search for connectivity between genes near the
associated SNPs, based on existing literature (published
before 2006 before the explosion of GWAS publications),
Figure 2 shows that of the 41 BP GWAS loci, 14 showed
underlying genes with significant relatedness, as defined
by the degree of similarity in the text describing them
within article abstracts, implying these connected genes
are involved in a common cellular process or pathway.
These regions of GRAIL connectivity show the expected
connection between NPPA/B and NPR3 but, in cases when
the GWAS SNPs lie in gene-rich regions, also reveal connections that point to specific novel genes for follow-up
studies. This is highlighted by rs805303, present in a very
gene-rich locus, and where a connection between NOTCH4

Trends in Genetics August 2012, Vol. 28, No. 8

and Jagged 1 (JAG1 in a different locus rs1327235)

highlights the NOTCH signaling pathway that has been
shown to be important in developing cardiovascular system and congenital human cardiovascular diseases. Their
connection with BP regulation is not intuitive, but this
association should prioritize this pathway and these genes
for functional dissection.
Despite the increasing pace of discovery of variants
associated with BP and HTN, the limited predictive utility
of these variants either singly or as part of a composite risk
score is striking. The population distribution of the number
of BP-increasing alleles with nearly similar allele frequencies is normally distributed because each SNP is inherited
independently, and hence the number of individuals in the
population that are expected to carry all harmful risk
alleles would be vanishingly small. As an example, using
the BP extreme casecontrol cohort [11], the probability
density functions of the number of BP-increasing alleles

TRENDS in Genetics

Figure 2. Representation of the connections between 41 BP GWAS SNPs and their corresponding genes using the GRAIL literature-based text-mining algorithm (Gene
Relationships Across Implicated Loci [34]). This searches for connectivity between genes near the associated SNPs, based on existing literature (we selected published
literature before 2006 before the surge of GWAS publications). The thickness of the red lines indicates the strength of the literature-based connectivity between the genes.
This type of analysis supports known interactions but also suggests new connections that are worth following up in future studies.

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Age>50 years
BP<120/80
No prevalent CVD or incident
CVD during 10 year follow-up
Hypertensive population
Age <63 years
BP>160/100

0.06

0.08

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0.00 0.02

0.04

Frequency

0.10

0.12

Review

30
35
40
45
50
Number of BP-increasing alleles
TRENDS in Genetics

Figure 3. For the prediction of complex diseases, genotypes at multiple SNPs are
often combined into scores (for example, scores are calculated according to the
number of risk alleles carried). The frequency distribution of the number of BPincreasing alleles carried in the general population would be normally distributed
because each allele is inherited independently. The frequency distributions of 35
BP-increasing alleles from GWAS SNPs in populations selected from the extremes
of BP distribution (top 9% and the bottom 2%) [11] show a large overlap of scores,
and the majority of the individuals from both phenotypic extremes lie in the middle
of the distribution. This illustrates the fallacy of using risk scores from GWAS SNPs
to identify individuals at high risk for hypertension. Abbreviation: CVD:
cardiovascular diseases.

(from 35 genome-wide significant GWAS SNPs) in hypercontrols and the extreme hypertensive cases are shown in
Figure 3, illustrating the significant overlap of cases and
controls by genetic risk score despite extremeness of the
phenotypic ascertainment. Using genetic risk scores constructed from up to 13 GWAS BP SNPs, a novel longitudinal study showed that individuals with the highest
combination risk score had significantly higher diastolic
BP at the age of nine years, and the effect was persistent
from childhood through adult age [35]. Genetic risk scores,
including many non-genome-wide significant SNPs,
explained more of the variance than scores based only
on very significant SNPs in adults and children
(1.21.7% in adults and 0.81.4% in children) [36].
Novel pathways uncovered by GWAS
Highly correlated SNPs (r2>0.9) in the 50 end of UMOD
have been independently identified in large GWAS of blood
pressure extremes and kidney function [11,16]. The UMOD
gene [expressed primarily in the thick ascending limb
(TAL) of the loop of Henle] encodes the TammHorsfall
protein [THP/uromodulin (UMOD)], an extracellular protein anchored by a glycosyl phosphatidylinositol (GPI)
functional group at the luminal face of tubular epithelia
and released into the urine by proteolytic cleavage. It is the
most abundant tubule protein in the urine. In the HTN
study, the minor G allele of rs13333226 at the 50 end of
UMOD gene is associated with a lower risk of HTN [OR
(95% CI): 0.87 (0.84;0.91); P = 3.61011], 0.49 mmHg
lower SBP (P = 2.6105) and 0.30 mmHg lower DBP
(P = 1.5105), increased estimated glomerular filtration
rate (eGFR) (3.6 ml/min/minor-allele, P = 0.012), reduced

urinary UMOD excretion and lower fractional excretion of

endogenous lithium. In addition, the genotype association
between rs13333226 and urinary UMOD excretion was
more pronounced with low salt intake and blunted with
high salt intake, indicating a possible geneenvironment
interaction [11]. Adjustment for eGFR in the HTN GWAS
did not alter the association between rs13333226 and
HTN. Mutations in UMOD cause medullary cystic kidney
disease type 2 (MCKD2), familial juvenile hyperuricemic
neuropathy (FJHN) and glomerulocystic kidney disease
(GCKD), but these only lead to HTN during latter stages of
renal failure. A single mechanism that could explain all the
observations involving the minor G allele of rs13333226 is
a decreased sensitivity of the macula densa to luminal Cl.
The decreased sensitivity of the macula densa may be
mediated either through the increased UMOD excretion
associated with the G allele or through other mechanisms.
Under this model, decreased macula densa sensitivity
activates tubuloglomerular feedback and increases GFR,
explaining the increased proximal tubular Na+ reabsorption. The lifetime effect of the elevated GFR would explain
the reduced BP and potentially the age-related effect of the
variant. There may be other possible mechanisms, for
example ROMK function is activated by UMOD, and thus
reduced ROMK activity might explain renal salt wasting in
THP knockout mice and patients with Bartter syndrome
[37].
Rare variants
Genes involved in monogenic hypertension are summarized in Table 1. Pseudohypoaldosteronism type II (Gordons syndrome; familial hyperkalemia; OMIM #145260),
an autosomal dominant form of HTN associated with
hyperkalemia, non-anion gap metabolic acidosis and increased salt reabsorption by the kidney, is caused by either
gain-of-function mutations in WNK1 or loss-of-function
mutations in WNK4. Recently, exome sequencing has been
used to identify mutations in kelch-like 3 (KLHL3) or
cullin3 (CUL3) in pseudohypoaldosteronism II (PHAII)
patients from 41 unrelated families [38].
Conversely, mutations that reduce salt retention, such
as those associated with Bartter (SLC12A1, KCNJ1,
CLCNKB, BSND, CaSR, ClCK-A) and Gitelman
(SLC12A3) syndromes, tend to lower BP and protect
against the development of HTN [39,40]. Resequencing
three candidate genes (SLC12A3, SLC12A1, KCNJ1) involved in Bartter or Gitelman syndromes in the Framingham Heart Study population identified 30 distinct
potentially deleterious rare mutations present in 49 subjects. In the heterozygous state, these variants were associated with 5.7 mmHg lower BP at age 40, and 9.0 mmHg
lower BP at age 60, and in aggregate reduce the risk of
HTN by 60% at age 60 [39]. This is the first indication that
rare variants can produce clinically significant BP reduction in the general population and supports the rarevariantcommon-disease hypothesis [41]. There are
currently exome sequencing projects involving individuals
at BP extremes to replicate this finding and discover more
rare variants with a large effect on blood pressure. The
hypothesis for these studies is that there will be an abundance of low-frequency variants of large effect that will
405

Review
explain most of the missing heritability of BP. Although the
clinical applications of these findings will be limited given
the very low frequency of these variants in the population,
these studies should uncover novel pathways and provide a
deeper understanding of the genetic architecture of blood
pressure.
Epigenetics
Not all features of gene regulation are encoded in genes or
contained in the DNA sequence. MicroRNAs (miRs), histone modifications and DNA methylation have all been
investigated with regard to their role in BP gene regulation. The potential role of miRs in vascular smooth-muscle
biology and blood pressure is just beginning to be appreciated. Mice lacking miR-143 and miR-145 develop significant reductions in BP resulting from modulation of actin
dynamics [42]. Intrarenal expression of miR-200a, miR200b, miR-141, miR-429, miR-205 and miR-192 were found
to be increased in hypertensive nephrosclerosis, and the
degree of upregulation correlated with disease severity.
There are significant correlations between miR species and
proteinuria and GFR, suggesting a doseresponse type of
relationship between intrarenal miR expression and the
severity of hypertensive nephrosclerosis [43]. Renin gene
expression appears to be regulated by miR-181a and miR663 [44]. The identification of these miRs may lead to the
elucidation of pathways involved in HTN causation and
novel therapeutics. Recently, an observational study
showed that human cytomegalovirus (HCMV) seropositivity and titers are positively associated with essential hypertension independently of other HTN risk factors [45].
The HCMV-encoded miR hcmv-miR-UL112 was highly
expressed in hypertensive patients, pointing to a potentially novel pathway involved in HTN. There is support
from an animal study showing that infection of mice with
mouse cytomegalovirus can alone elevate blood pressure
[46]. Although this is an observational finding, it highlights
the prospect of an abundance of pathways and risk factors
that lead to the final common BP phenotype and may have
implications for the discovery of new treatments.
Recently, renal sympathetic denervation has shown
considerable promise in treating refractory HTN [47].
The sympathetic innervation of the kidney is implicated
in the pathogenesis of HTN by increasing plasma renin
activity that leads to sodium and water retention and
reduces renal blood flow (RBF). The procedure involves
radiofrequency ablation of the renal sympathetic nerves,
and has shown remarkable reductions in BP, but the
underlying mechanism is unclear. Recently, histone modification has been shown to play an important role in the
epigenetic modulation of WNK4 transcription in the development of salt-sensitive HTN. Isoproterenol-induced transcriptional suppression of WNK4 was shown to be
mediated via inhibition of histone deacetylase-8 activity
(HDAC8) at the WNK4 promoter [48], which in turn can
stimulate thiazide-sensitive Na+-Cl+ cotransporter (NCC/
SLC12A3) implying that sympathetic nerve activity can
increase BP partly by activating NCC. The evidence that
isoproterenol induces transcriptional suppression of
WNK4 and leads to activation of NCC offers an opportunity
to combine genomics, epigenomics and NCC detection in
406

Trends in Genetics August 2012, Vol. 28, No. 8

urinary exosomes to test the saltsympathetic-systemBP

axis [48,49].
There are indications of epigenetic regulation involving
interactions between a disruptor of telomeric-silencing
alternative splice variant a (Dot1a) and the ALL-1 fused
gene from chromosome 9 (Af9) to produce a nuclear repressor complex that targets histone H3 Lys-79 methylation in
the promoter region of the sodium channel SCNN1A and
suppresses its transcriptional activity [50]. Aldosterone
can disrupt this nuclear complex, which results in histone
H3 Lys-79 hypomethylation at specific subregions and
derepression of the SCNN1A promoter. This adds a novel
epigenetic dimension to the complex transcriptional and
post-transcriptional regulation of the epithelial sodium
channel by aldosterone.
Concluding remarks
Unraveling the genetic basis of BP regulation and HTN has
been more difficult than might be suggested by their high
heritability, but the progress in cataloging common variants using GWAS is comparable to other common traits.
Ongoing studies include the GWAS meta-analysis of BP
extremes and exome sequencing of BP extremes to identify
more sequence variants that are associated with BP. Indeed, it has been estimated that further increasing the
GWAS sample size will identify 116 common variants for
BP that have similar effect sizes to those found already, but
these will collectively explain only about 2.2% of the phenotypic variance [6].
Some important issues to be addressed in future studies
investigating BP as a quantitative trait are to model BP
more accurately in subjects on antihypertensive treatments by taking into account the number of drugs, drug
dosage and compliance metrics, or to make use of longitudinal BP data for example long-term average and BP
variability (both visit-to-visit or 24 h intra-individual variability). Novel strategies and orthogonal study designs are
needed to discover causal and clinically useful genetic
markers efficiently. This would require a move from pure
BP quantitative traits in larger and larger cohorts to
detailed studies of subjects selected on informative intermediate traits derived from the extensive interventional
studies for high BP. SNPs near the genes encoding uromodulin and natriuretic peptides show allelic association
with urinary uromodulin and plasma natriuretic peptides
respectively [11,31] and offer the opportunity for saltintervention trials to dissect the underlying mechanisms
further. Randomized clinical trials with stored DNA samples offer a readily available resource to study not only
drug response but also to dissect pathways of HTN based
on interindividual differences in response to drugs that
target specific pathways.
The limited predictive utility of common variants that
have emerged from most GWAS would suggest that to
build better predictive models it will be necessary to identify orthogonal (i.e., uncorrelated) genetic variants that are
associated with new pathways as suggested for biomarkers
[51]. The current despondency over poor prediction is
probably related to the early discovery of low-hanging fruit
that are perhaps more correlated with known pathways.
The next level of discovery will be more challenging

Review
because the molecular and functional dissection of the
novel variants will require more detailed low-throughput
science in contrast to the high-throughput screening
methods applied so far.
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