(Circulation. 2000;101:2810.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
QTL Influencing Blood Pressure Maps to the Region of PPH1 on Chromosome 2q31-34 in Old Order Amish
From Southwest Foundation for Biomedical Research, San Antonio, Tex (W.-C.H., B.D.M., J.L.S.); GlaxoWellcome, Inc, Research Triangle Park, NC (M.J.W.); Axys Pharmaceuticals, La Jolla, Calif (C.J.B., E.N.); and the University of Maryland School of Medicine, Baltimore (A.R.S.).
Correspondence to Braxton D. Mitchell, Department of Genetics, Southwest Foundation for Biomedical Research, PO Box 760549, San Antonio, TX 78245-0549. E-mail bmitchel{at}darwin.sfbr.org
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Background—Hypertension is a major risk factor for coronary heart disease, stroke, congestive heart failure, renal insufficiency, and peripheral vascular disease. Although the genetic contribution to variation in blood pressure is well recognized, the specific genes involved are mostly unknown. We carried out a genome-wide scan to identify loci influencing blood pressure in the Old Order Amish population of Lancaster County, Pennsylvania.
Methods and Results—Blood pressures were measured in 694 adult participants from families recruited without regard to blood pressure. We performed a quantitative linkage analysis by using 357 microsatellite markers. In multipoint analysis, strong evidence for linkage was observed with both diastolic (lod=3.36; P=0.00004) and to a lesser extent systolic (lod=1.64; P=0.003) blood pressure in the region of chromosome 2q31-34. Peak evidence for linkage occurred at map positions 217 and 221 cM from pter for diastolic and systolic blood pressure, respectively.
Conclusions—A gene linked to familial primary pulmonary hypertension has recently been mapped to this same region, suggesting the intriguing hypothesis that other (attenuated) mutations in this same gene may influence variation in systolic and diastolic blood pressure in this population.
Key Words: blood pressure • Amish • genetics • hypertension, pulmonary
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Introduction |
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Hypertension is one of the most common chronic diseases in the United States, affecting 20.4% of adults 18 to 74 years of age and nearly three quarters of African Americans and one half of whites 60 to 74 years of age.1 It is a major risk factor for coronary heart disease, stroke, congestive heart failure, end-stage kidney disease, and peripheral vascular disease2 and consequently results in tremendous disability and mortality rates.
Variation in blood pressure is influenced by both genetic and environmental factors.3 4 Although several rare simple mendelian forms of hypertension have been described,3 no underlying cause or transmission pattern can be readily discerned in the vast majority of patients with hypertension. Most family studies indicate that genes account for 20% to 40% of the variation in blood pressure levels.5 6 7 To date, however, there has been little progress in identifying the specific genetic defects responsible for the common forms of hypertension.
To identify specific loci influencing variation in blood pressure, we conducted a genome-wide scan in the Old Order Amish (OOA), a genetically isolated white population characterized by large family sizes.
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Methods |
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The OOA population originated in Western Europe (mainly Switzerland), when followers of Jacob Ammann split from their parent Anabaptist sect and emigrated to the United States to escape religious prosecution over a 50-year period beginning in 1727.8 Approximately 200 pioneer couples settled in Lancaster County, Pennsylvania, and may be considered founders of the present group of the Lancaster Amish.9 The number of OOA in the area is >30 000 today,10 and nearly all surviving members can be linked to a single 14-generation pedigree.11 The OOA are a rural-living population and are characterized by their eschewal of technological innovation and strong interest in their ancestry and genealogical relationships. Furthermore, there is considerable homogeneity in the Amish lifestyle. The majority of men are farmers and the women are mostly homemakers. Fewer than 3% of the OOA report that they currently smoke, and nearly 90% of our study participants reported not having any leisure physical activities. Alcohol consumption is minimal. The OOA do not practice birth control, and family members usually eat their meals together.
With the support of the Amish community, recruitment for the Amish
Family Diabetes Study began in early 1995 with the goal of identifying
susceptibility genes for type 2 diabetes and related traits. The study
protocol was approved by the Institutional Review Board at the
University of Maryland School of Medicine, and informed consent was
obtained from each study participant. With the help of liaisons from
the OOA community, we identified individuals with type 2 diabetes.
These probands and their family members 
18 years of age were
recruited into the study. Between February 1995 and February 1997, 694
subjects received examinations at the Amish Diabetes Research Clinic in
Strasburg, Pennsylvania. Appointments were made in advance by home
visit, since the Amish do not use telephones or cars. At the clinic,
study subjects received an extensive interview regarding their personal
medical history and family history of diabetes. Anthropometric
measurements and a 3-hour, 75-g oral glucose tolerance test were also
performed. Systolic blood pressure (SBP) (1st phase) and
diastolic blood pressure (DBP) (5th phase) levels were
obtained in duplicate with the use of a standard sphygmomanometer with
the patient sitting for 5 minutes and were recorded to the
nearest 1 mm Hg. Body mass index (BMI) was calculated as weight
(kg) divided by height squared (m2).
Mean blood pressure and prevalence of hypertension (SBP 140
mm Hg or DBP 90 mm Hg or current use of antihypertensive
medications) were compared between the Amish population and a
representative sample of the overall white population
in the United States, as assessed by the National Health and Nutrition
Examination Survey (NHANES) III, conducted during 1988 to
1991.1
DNA was extracted from leukocytes, and a screening set of 357 highly polymorphic microsatellite short tandem repeat markers was genotyped from the ABI Prism Linkage Mapping Set (Perkin-Elmer). The mean marker heterozygosity was 0.75, ranging from 0.33 to 0.91. The average interval between markers was 10.2 cM, and the largest gap between markers was 25.4 cM, occurring on chromosome 7.
Quantitative trait linkage analysis was carried out with the
use of a variance components methodology, in which we partitioned
variation in blood pressure into components attributable to
environmental covariates, the additive effects of genes (ie, residual
heritability), and a specific quantitative trait locus, or QTL (ie, the
linkage component). These analyses were conducted with the use
of maximum likelihood procedures as implemented in the SOLAR software
package.12 The additive genetic effect was modeled as a
function of the expected genetic covariances between relatives,
and the QTL effect was modeled as a function of the identity by descent
relationships at the marker locus. The hypothesis of linkage is
evaluated by the likelihood ratio test, in which one evaluates whether
the locus-specific effect is significantly >0 (ie,
Ho:
2QTL=0 versus
HA:
2QTL>0). Both multipoint and
2-point linkage analyses were carried out. SBP and DBP were
analyzed separately, and in each analysis, we
simultaneously adjusted for the effects of sex and
sex-specific age and age2 . Individuals currently taking
antihypertensive medications (n=33) were excluded from
analysis. Thus, the total number of individuals included for
linkage analysis was 661.
We derived the distribution of nominal lod scores under the null
hypothesis of no linkage empirically by simulation. To generate this
distribution, we simulated an unlinked marker locus with 5 equifrequent
alleles, assigned genotypes to each founder, and then
dropped genotypes down through the pedigree based on mendelian
expectations and the founder genotypes. The simulated unlinked
marker had approximately the same information content (ie,
heterozygosity=80%) as the markers used in the genome scan. We then
conducted linkage analysis of blood pressures with the
simulated unlinked marker. The unlinked marker locus was simulated with
the use of PAP4 software,13 and the linkage
analysis on each simulated data set was carried out with the
use of the SOLAR software program. We conducted 20 000 replicates and
defined the probability of obtaining a false-positive result as the
proportion of replicates for which we obtained a specified lod score or
higher. These probabilities were then converted into lod scores by
first converting them into 
2 values, and then dividing
the 2 statistic by (2·loge10). All
lod scores presented in this article were obtained from this
simulation.
Although all subjects can be related by tracing their ancestors back multiple generations, to reduce computational difficulties, we divided the sample into 28 discrete families, ranging in size from 3 to 69 individuals. The sample included a large number of relative pairs, including 436 parent-offspring pairs, 1326 sib-pairs, 1342 avuncular (aunt/uncle-niece/nephew) pairs, and 1311 first-cousin pairs.
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Results |
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The mean age of the 694 participating study subjects was 46.5±15.7 years, and mean levels of SBP and DBP were 122.4±17.8 mm Hg and 78.4±9.7 mm Hg, respectively. Mean BMI was higher in women than in men (28.0±5.7 versus 26.2±3.8 kg/m2). Mean blood pressures for men and women are shown in Figure 1
for both the OOA
and the overall US white population. Among men, blood pressures were
similar in the OOA compared with the overall US white male population,
but OOA women tended to have slightly higher blood pressures than the
overall US white female population. In general, the prevalence of
hypertension in the OOA women (21.7%) was comparable to that in the US
white women, although the prevalence in OOA men (16.1%) is slightly
lower than in US white men. The age-specific prevalence rates of
hypertension in the OOA are shown in Figure 2. The level of hypertension control in
the OOA was low, with only 25% of hypertensive subjects currently
under treatment, compared with >50% in the overall US white
population.
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Heritabilities of SBP and DBP were 0.23±0.07 (P<0.0001)
and 0.29±0.07 (P<0.0001), respectively, indicating that a
substantial portion of the variation in these traits is attributable to
additive genetic factors. Detailed results from our multipoint
genome-wide scan are shown in Figure 3.
(These results may also be obtained from the SFBR web site at
http://www.sfbr.org/sfbr/departments/genetics/genepid/). The maximum
lod scores were 3.36 and 1.64 for DBP and SBP, respectively, both
occurring in the same region on chromosome 2q, 
217 to 221 cM from
pter. On only 1 other chromosome did we obtain a lod score as high as
1.0 (lod score=1.49 for DBP on the pter end of chromosome 9).
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Results from the multipoint linkage analysis for chromosome 2
are shown in Figure 4. Peak evidence for
linkage for both SBP and DBP occurred in the region bounded by markers
D2S117 and D2S325. The 1-lod unit support interval (ie, the region
corresponding to the peak lod score minus 1) for the region
encompassing the DBP QTL included a 17-cM interval flanked by markers
D2S364 and D2S325, and that for SBP included a 35-cM interval flanked
by markers D2S326 and D2S126. The addition of diabetes and BMI as
covariates did not substantially alter these results (adjusted lod
scores=3.63 and 1.32 for DBP and SBP, respectively, at these same
marker positions). There was no evidence for linkage of the dichotomous
trait, hypertension, to chromosome 2q markers (data not shown),
although the power to dtect linkage to the dichotomous
trait was low in this sample.
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A second region of suggestive linkage to SBP (lod=1.09) was also
observed on chromosome 2, 56 cM from pter on the short arm. A
conditional analysis was performed to determine whether the
effect of allele-sharing at this second locus accounted for a
significant portion of the trait variation, after accounting for
allele-sharing at the locus on chromosome 2q. This hypothesis was
evaluated by the likelihood ratio test, in which we compared the
likelihood of a 2-locus model (ie, QTL effects at chromosome 2p and 2q)
with that of a 1-locus model (QTL effect at chromosome 2q only). The
likelihood of the 2-locus (conditional) model was only marginally
better than that of the likelihood of the single-locus model, with the
marginal lod score of the 2p locus estimated to be only 0.20.
The 2-point linkage analyses provided substantial supporting evidence for linkage of both SBP and DBP to the 20-cM region on chromosome 2q. Three markers were typed within the region of linkage: D2S364 (at 205.2 cM from pter), D2S117 (at 214.6 cM from pter), and D2S325 (at 224.4 cM from pter). The 2-point lod scores associated with these markers were (for DBP and SBP, respectively) 1.41 and 0.81 for D2S364; 3.13 and 1.33 for D2S117; and 1.91 and 1.49 for D2S325.
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Discussion |
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The results from our analyses provide strong evidence for the presence of a gene on the long arm of chromosome 2 that influences variation in systemic blood pressure. This conclusion is bolstered by the fact that linkage was detected in this same region to both DBP and SBP and that consistent evidence for linkage across multiple markers in this region was obtained in the 2-point analyses. The evidence for linkage, as determined by simulation studies, was P=0.00004 for DBP and P=0.003 for SBP (corresponding to lod scores of 3.36 and 1.64 for DBP and SBP, respectively). We detected virtually no other linkage signals for either trait anywhere else in the genome. Considering that the correlation between SBP and DBP in this population is 0.65, it is possible that a locus on chromosome 2q influences variation in both traits. There are, however, almost certainly additional loci elsewhere in the genome that contribute to variation in either SBP or DBP (or both).
Despite the unique background of the OOA, epidemiological aspects of
blood pressure variation in this population appear very similar to the
overall US white population. For example, the distribution of blood
pressure levels and the prevalence of hypertension in the Amish are
comparable to those of the US white population. Furthermore, as in
other populations, blood pressure variation in the Amish has a
significant familial component, but there is no clear mode of
inheritance. Since the Lancaster County OOA arose from 200 founding
couples who migrated to the United States from Western Europe in the
early to mid 1700s, and a subset of the overall US gene pool also
originated from this region of Europe, we hypothesize that common gene
variants that contribute to blood pressure variation in the Amish are
likely to comprise a subset of those that are relevant in the overall
US and European white populations. It is possible that the unique
characteristics of the OOA population may favor detection of these
blood pressure genes since there may be a smaller number of genetic
variants segregating in this population, each contributing a greater
proportion of variation in blood pressure. In addition, the relatively
homogenous lifestyle of the Amish may further make these gene variants
easier to detect, since they will account for a larger component of the
trait variation. Proof of these hypotheses will require the
identification of specific gene variants through positional cloning or
positional candidate approaches.
Linkage has previously been reported between hypertension (and/or blood
pressure) and several functional candidate genes, including
angiotensinogen on chromosome 1q42-43,14 15
1B-adrenergic receptor and dopamine receptor
type 1A on chromosome 5q31.1-qter,16 lipoprotein lipase on
chromosome 8p22,17 genes encoding the ß and 
subunits
of epithelial sodium channel on chromosome 16p12,18 and
angiotensin-converting enzyme on chromosome
17q23.19 20 Two recent genome-wide linkage studies using
discordant sib-pairs found several linkage signals on 2p21-22.1,
5q33.3-34, 6q23.1-24.1, and 15q25.1-26.121 and regions
containing markers D3S2387, D11S2019, D15S657, D16S3396, and
D17S1303.22 However, there was no evidence in our
analysis for linkage of any of these regions to blood pressure
variation. Linkage to blood pressure variation has been reported in
several studies with rodent models,23 24 25 26 27 but none of
these maps to human chromosome 2.
The fact that we failed to detect linkage to any of these regions in
the OOA can be attributed to any of a number of factors, including the
possibility that the prior results were false-positives and the lack of
power of our study to detect linkages observed in other populations. We
estimated the power of our sample to detect QTL effects that accounted
for 10% to 30% of the phenotypic variation in blood pressure in our
population. These results, obtained by simulation, revealed that we
would have 78% power (at lod3) to detect a QTL that accounted for
30% of the phenotypic variation, 56% power to detect a QTL accounting
for 25% of the phenotypic variation, and 33% power to detect a QTL
accounting for 20% of the phenotypic variation. Thus, even if these
other gene effects did exist, our power to detect them would be low.
Our power to detect linkage to the qualitative trait, hypertension, was
far lower, as the number of affected sib-pairs in our sample was 92, 71
(77%) of whom come from only 6 sibships, thus making the number of
independent sibships substantially lower.
There are, in addition, substantial differences in study design and
analytic strategies between our studies and others that may also
account for the failure of our study to detect linkages reported by
others. For example, some of the published studies (except for 2 recent
discordant pair analyses21 22 ) did not test for
linkage genome-wide but rather evaluated evidence for linkage only to a
set of hypertension candidate genes, none of which were on chromosome
2q. Some studies have evaluated evidence for linkage to the dichotomous
trait hypertension only,15 whereas others have reported
results for SBP only.16 21 Although it is likely that
there may be genes with pleiotropic effects on all 3 traits, it is also
possible that there are genes whose influence is primarily on 1 of
these traits. A further key difference among published studies is the
age distribution of the population. Different genes may express their
effects at different ages, or their effects may be expressed only in
the presence of other age-related factors, as, for example, long-term
smoking exposure and/or hormonal profile. In our study, the majority of
subjects were 40 years of age, whereas at least 2 other genome scan
studies have focused primarily on younger subjects.21 22
The high proportion of postmenopausal women in our sample may have
added an additional source of variability into our study, since
different genes may influence blood pressure regulation in the
premenopausal and postmenopausal states.
Recently, 2 different groups have independently localized a gene for
familial primary pulmonary hypertension (PPH) to a 25-cM region
on 2q31-32, an interval corresponding closely to the peak region of
linkage in our analysis.28 29 PPH is a rare
disease characterized by elevated pulmonary artery pressures in
the absence of a secondary cause.30 The disorder leads to
right ventricular failure and, in the absence of treatment,
death. Young women are at higher risk for the disorder, and an
estimated 6% of PPH cases are inherited in an autosomal dominant
fashion with reduced penetrance.31 In 1997, Nichols et
al28 identified 6 families in which familial PPH was
segregating and reported a maximum multipoint lod score of 7.86,
occurring at the map position of marker D2S311. On our map, this marker
falls within the interval flanked by markers D2S117 and D2S325, the 2
markers that flank the peak region of linkage in our analysis.
In fact, Nichols et al place the location of marker D2S311 at 1.6 cM
telomeric to marker D2S117, a position corresponding to position 216.8
cM from pter on the Amish map. Thus, our peak signal for DBP in
multipoint analysis occurred at a position <1 cM away from the
point of peak linkage reported by Nichols et al, and our peak signal
for SBP occurred at a position 4 cM away. At about the same time,
Morse et al29 observed significant evidence for linkage
(lod=3.87) with markers in this same region in a single family with
autosomal dominant PPH. These investigators mapped the PPH1
locus to a 27-cM region flanked by markers D2S1776 and D2S1384, with
peak evidence for linkage also occurring at marker D2S311, but with 6
additional markers (including D2S364) on the centromeric side of D2S311
also providing equally strong evidence for linkage.
To date, PPH1 has not been cloned, nor is its function
known. An autoimmune component to the underlying cause of PPH has been
suggested on the basis of reported associations between PPH and several
autoimmune disorders30 32 and with specific HLA
alleles.33 34 The candidate region encompassing
PPH1 contains other known genes that could influence
vascular wall function, such as parathyroid receptor 2 and insulin
growth factor binding proteins 2 and 5. In addition, a cluster of
immunoglobulin superfamily genes that encode integrin subunits v,
4, and ß6 has been localized to this
region.35 36 37
To our knowledge, there have been no OOA families with PPH. Nevertheless, it is intriguing to speculate that the QTL identified in our analysis of blood pressure variation in the Amish may, in fact, be PPH1, or a linked regulator of this gene. Although PPH is a rare disease (with only 60 families identified in the United States since 1954 as having >2 affected family members),28 it is possible that other defects in this gene may produce a phenotype of systemic blood pressure elevation by affecting systemic endothelial vasculature and/or function.
The results of this genome-wide scan to detect blood pressure genes have revealed the presence of a QTL on chromosome 2q in the OOA that influences DBP and perhaps also SBP. The point of peak linkage coincides closely with the location of PPH1. The identification of this gene, whether it turns out to be PPH1 or a closely linked gene, should enhance our understanding of the cause of hypertension and perhaps lead to novel strategies for the prevention and treatment of this disease.
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Acknowledgments |
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This work was supported by research grants from Glaxo Wellcome Inc and Axys Pharmaceuticals.
Received September 7, 1999; revision received January 5, 2000; accepted January 25, 2000.
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 P. Duggal, A. P. Klein, K. E. Lee, S. K. Iyengar, R. Klein, J. E. Bailey-Wilson, and B. E. K. Klein A Genetic Contribution to Intraocular Pressure: The Beaver Dam Eye Study Invest. Ophthalmol. Vis. Sci., February 1, 2005; 46(2): 555 - 560. [Abstract] [Full Text] [PDF]
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M. de Lange, T. D. Spector, and T. Andrew Genome-Wide Scan for Blood Pressure Suggests Linkage to Chromosome 11, and Replication of Loci on 16, 17, and 22 Hypertension, December 1, 2004; 44(6): 872 - 877. [Abstract] [Full Text] [PDF]
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 C. A. Mein, M. J. Caulfield, R. J. Dobson, and P. B. Munroe Genetics of essential hypertension Hum. Mol. Genet., April 1, 2004; 13(90001): R169 - 175. [Abstract] [Full Text] [PDF]
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R. A. Barkley, A. Chakravarti, R. S. Cooper, R. C. Ellison, S. C. Hunt, M. A. Province, S. T. Turner, A. B. Weder, E. Boerwinkle, and on behalf of the Family Blood Pressure Program Positional Identification of Hypertension Susceptibility Genes on Chromosome 2 Hypertension, February 1, 2004; 43(2): 477 - 482. [Abstract] [Full Text] [PDF]
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 S. Oparil, M. A. Zaman, and D. A. Calhoun Pathogenesis of Hypertension Ann Intern Med, November 4, 2003; 139(9): 761 - 776. [Full Text] [PDF]
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N. J. Camp, P. N. Hopkins, S. J. Hasstedt, H. Coon, A. Malhotra, R. M. Cawthon, and S. C. Hunt Genome-Wide Multipoint Parametric Linkage Analysis of Pulse Pressure in Large, Extended Utah Pedigrees Hypertension, September 1, 2003; 42(3): 322 - 328. [Abstract] [Full Text] [PDF]
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F. von Wowern, K. Bengtsson, C. M. Lindgren, M. Orho-Melander, F. Fyhrquist, U. Lindblad, L. Rastam, C. Forsblom, T. Kanninen, P. Almgren, et al. A genome wide scan for early onset primary hypertension in Scandinavians Hum. Mol. Genet., August 15, 2003; 12(16): 2077 - 2081. [Abstract] [Full Text] [PDF]
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 A. C. Morrison, A. Brown, S. L.R. Kardia, S. T. Turner, and E. Boerwinkle Evaluating the Context-Dependent Effect of Family History of Stroke in a Genome Scan for Hypertension Stroke, May 1, 2003; 34(5): 1170 - 1175. [Abstract] [Full Text] [PDF]
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 W.-C. Hsueh, P. L. St. Jean, B. D. Mitchell, T. I. Pollin, W. C. Knowler, M. G. Ehm, C. J. Bell, H. Sakul, M. J. Wagner, D. K. Burns, et al. Genome-Wide and Fine-Mapping Linkage Studies of Type 2 Diabetes and Glucose Traits in the Old Order Amish: Evidence for a New Diabetes Locus on Chromosome 14q11 and Confirmation of a Locus on Chromosome 1q21-q24 Diabetes, February 1, 2003; 52(2): 550 - 557. [Abstract] [Full Text] [PDF]
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J. S. Cui, J. L. Hopper, and S. B. Harrap Antihypertensive Treatments Obscure Familial Contributions to Blood Pressure Variation Hypertension, February 1, 2003; 41(2): 207 - 210. [Abstract] [Full Text] [PDF]
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R. S. Cooper, A. Luke, X. Zhu, D. Kan, A. Adeyemo, C. Rorimi, N. Bouzekri, and R. Ward Genome Scan Among Nigerians Linking Blood Pressure to Chromosomes 2, 3, and 19 Hypertension, November 1, 2002; 40(5): 629 - 633. [Abstract] [Full Text] [PDF]
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T. A. Kotchen, U. Broeckel, C. E. Grim, P. Hamet, H. Jacob, M. L. Kaldunski, J. M. Kotchen, N. J. Schork, P. J. Tonellato, and A. W. Cowley Jr Identification of Hypertension-Related QTLs in African American Sib Pairs Hypertension, November 1, 2002; 40(5): 634 - 639. [Abstract] [Full Text] [PDF]
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 T. Rankinen, P. An, L. Perusse, T. Rice, Y. C. Chagnon, J. Gagnon, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, et al. Genome-wide linkage scan for exercise stroke volume and cardiac output in the HERITAGE Family Study Physiol Genomics, August 14, 2002; 10(2): 57 - 62. [Abstract] [Full Text] [PDF]
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S. C. Hunt, R. C. Ellison, L. D. Atwood, J. S. Pankow, M. A. Province, and M. F. Leppert Genome Scans for Blood Pressure and Hypertension: The National Heart, Lung, and Blood Institute Family Heart Study Hypertension, July 1, 2002; 40(1): 1 - 6. [Abstract] [Full Text] [PDF]
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T. Rice, T. Rankinen, Y. C. Chagnon, M. A. Province, L. Perusse, A. S. Leon, J. S. Skinner, J. H. Wilmore, C. Bouchard, and D. C. Rao Genomewide Linkage Scan of Resting Blood Pressure: HERITAGE Family Study Hypertension, June 1, 2002; 39(6): 1037 - 1043. [Abstract] [Full Text] [PDF]
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K. Kristjansson, A. Manolescu, A. Kristinsson, T. Hardarson, H. Knudsen, S. Ingason, G. Thorleifsson, M. L. Frigge, A. Kong, J. R. Gulcher, et al. Linkage of Essential Hypertension to Chromosome 18q Hypertension, June 1, 2002; 39(6): 1044 - 1049. [Abstract] [Full Text] [PDF]
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S. B. Harrap and S. Petrou Utility of genetic approaches to common cardiovascular diseases Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H1 - H6. [Full Text] [PDF]
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T. Rankinen, P. An, T. Rice, G. Sun, Y. C. Chagnon, J. Gagnon, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, et al. Genomic Scan for Exercise Blood Pressure in the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study Hypertension, July 1, 2001; 38(1): 30 - 37. [Abstract] [Full Text] [PDF]
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S. B. HARRAP, Z. Y. H. WONG, M. STEBBING, A. LAMANTIA, and M. BAHLO Blood pressure QTLs identified by genome-wide linkage analysis and dependence on associated phenotypes Physiol Genomics, February 28, 2002; 8(2): 99 - 105. [Abstract] [Full Text] [PDF]
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