Download Genetically Complex Cardiovascular Traits

145
Workshop on Molecular Genetic Analysis of Hypertension
and Cardiovascular Disease
Genetically Complex Cardiovascular
Traits
Origins, Problems, and Potential Solutions
NtcholasJ Schork
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Abstract Modern molecular genehc analysrs tools are makmg rt possible for researchers to mvesttgate, and m many cases
actually disclose, mutattons and other genetic factors that contribute to disease susceptrbrhty However, the ease with which
these factors can be rdentrfied IS dictated by not only the number
of factors underlymg or mfluencmg the trait, but also by the manner m which these factors interact Traits that are influenced by
multrple genetic and nongenetic factors are termed “complex”
genetictraits andare receivinga greatdealof attentionin the
current medical literature Hypertension and blood pressure regulatton are considered paradigmatic complex trmts In this paper,
the origin, nature, and dilemmas associated wtth the analysts of
complex traits are considered Basic brochemrcal and physrologrcal determinants of blood pressure are described m an effort to
T
he searchfor genesinfluencing traits and diseases
of all sorts hasbecomethe focal point of a great
deal of contemporary medicalresearch.1The reason for thts is obvious* If a gene contnbutmg to a malleable, preventable, or treatable condition can be identified, then that gene’sstructure, function, and ultimate role
m mfluencmg the relevant condttlon can be determined
This knowledge could lead to better ways of predictmg
the (future) presence of that condmon, diagnosing that
condition, and preventmg (or enhancing) that condition
It should be no surprisethat most of the researchin this
area hasfocused on diseasesthat are debihtatmg or common sourcesof morbidtty and mortahty in the population
at large Hypertension and relatedcardiovasculardiseases
are maJorcontributors to morbidity and mortahty m modern industrial and urbanized societiesand have thus received considerableattention from geneticists Unfortunately, suscepttbilmesto hypertension and us sequelae
are known to be mediated by a number of genetic and
nongenetic factors This fact makeshypertensive cardiovascular disease(HCD) paradigmattc of so-called “complex” genetic traits. Although the label “complex trait”
has been used mdtscrlmmately and could be applied,
From the Department of Eprdemrology and Brostatrstrcs and the
Department of Genetics, Case Western Reserve Unrversny, Cleveland, Ohio, the Department of Brostatrstrcs and the Program for Population Genetics, Harvard Unrversrty School of Pubhc Health, Boston, Mass, and The Jackson Laboratory, Bar Harbor, Me
Supported by NIH grants HL94-011 (NHLBI), HL54998-01
(NHLBI), and RR03655-11 (NCRR)
Correspondence to Nicholas J Schork, PhD, Department of Eprdemtology and Brostatrstrcs, Case Western Reserve Umversrty, R215
Rammelkamp Burldmg, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109-1998 E-marl nJs2@po cwru edu
Q 1997 American Heart Assocratron, Inc
show how genetic complexrty could artse wtthm an mdrvrdual,
and fundamental concepts m populatton genetics and evoluttonary theory are discussed to expose the reasons certain forms of
genetic complextty can emerge and be sustained m the populatton
at large Methods for approaching the genetic dtssectton of complex trnts and diseases are also enumerated, with sample descrtpttons of the screntrfic motrvatton offered for each Problems
plagumg these approaches are also discussed Fmally, areas for
future research are outlined with the hope of sparkmg further
debate on the subJect. (Hypertension. 1997;29[part 2]:145-149.)
Key Words l linkage analysts l stattsttcal models
mapping l complex traits l genetic eprdemrology l
Wright l evolutron
l
gene
Sewail
given its vagueness,to any trait, disease,or condition, the
true hallmark feature of a complex tract as mmally defined’ is an underlying determmatton that can only be
attributed to multiple genes and envuonmental factors
With this m mmd, it is thought that the dtsclosure and
characterization of the factors contributing to the emergenceand mamtenanceof complex traits will require very
sophtsttcatedresearch strategtes.r-3Many of the extant
strategiesfor dissectingthe geneticbasisof complex traits
are inadequateand not very powerful. This is hkely due
to the fact that not much tune has elapsedbetween the
mventton of molecular tools that could be used to probe
for genesand the present state of medical research It is
therefore important to consider issuesthat might be of
relevance for the development of better research strategiesthat make use of thesetools
In this article a discussionof the ongms of, problems
associatedwith, and researchavenues for mvesttgatmg
complex HCD is offered. A crucial dlstmctlon between
complexity at the level of an mdivtdual and complexity
at the level of a population is made. It is hoped that by
discussingissuessurroundmgthe very defimtron, origm,
and problems associatedwtth complex genetic disease
research,a greater focus on appropriate researchstrategies for HCD will emerge. A more complete discussion
of relevant issuesdeveloped m this article is given by
N J. Schork (m preparatton).
Complexity of Complex Traits: Individuals
Humanphysiology andbiochemistryareextremely complex Nowhere 1sthis clearer than m the regulation of
human blood pressure Consider Fig 1, which offers an
abstractionof the factors medtatmg blood pressurelevel
wrthm an mdrvrdual.
It 1s clear that an rndmdual’s
blood
pressurelevel ISinfluenced by a host of systemsand sub-
Hypertension
146
Vol29,
No 1, Part
-
2
January
RAS(eg)
1
hormones
\
Vasosctive
=
-
Carblac
Stroke
Volume
/\
End
Dlasc
-
Valve
Defects
A
I\
output
x
End
Systole
c-
x
HimI
Rate
,
Total Peripheral
A
t
1
Catecholamines
MAP
1997
I
Resistance
A
Vessel
Et./
VenousTone
t
I
structure
-
Atherogenesls
t
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
FIG 1 SchematIc
diagram
of factors
lnfluenclng
mean arterial
blood pressure
(MAP) regulation
Note that MAP IS defined
as
the mathematical
product
of cardiac output (CO) and total peripheral resistance
(TPR), whereas
cardiac output IS itself defined
as the mathematical
product
of heart rate and stroke volume
Arrows show the Impact of “subsystems”
on more abstract systems Note also that each subsystem
influencing
blood pressure
regulation
or level may be Influenced
by further factors
Arrows
with no deslgnatlon
simply characterize
additional
biochemical
or
physiological
subsystems
This diagram illustrates the well-known
fact that a large number of biochemical
and physiological
pathways
determine
the blood pressure
level of an lndlvldual
These pathways Include autoregulatoty
mechanisms
(AMs), which are invoked
by the central nervous
system to stabilize an individual’s
blood
pressure level when a single factor IS upset Thus, If an indmdual’s
TPR IS raised due to a mutation
that results in, eg, norepinephnne
overproduction,
an AM might be Invoked to lower CO The multlple
pathways
mediating
blood pressure control create great potential
for different
genes, when upset due to mutation
or a variation, to
have a deleterious
Impact on blood pressure
level
systems, all interwoven mto a complex network that IS
simultaneously filled with hierarchies and redundancies
On top of this network are additional phenomena, such as
development, growth, and aging, which might further
complicate blood pressure regulation, since each system
or subsystem may have a more or less pronounced effect
on an mdlvldual’s blood pressure level at different times
m the life of that mdlvldual. This multitude of systems and
age dependencies creates enormous potential for a variety
of mutant genes to upset or impact blood pressure level
Identification of such genes through classtcal genetic strategies that involve studying hypertensive mdlvlduals or mdlvlduals with HCD will then be plagued by this very redundancy, compensatory control, and factors like them
This IS the case simply because the effect of any one gene
may be obscured or confounded by the effects of others
There are at least five problems plaguing the ldentlfication of genes underlying complex traits that have received recent attention
(1) ClassIcal polygemc or “threshold” mhentance, m
which a number of genotypes or mutations at different loci
(which likely impact different physlologlcal systems) must
be transmitted to an mdlvldual before his or her system 1s
sufficiently challenged to result m disease Thus, despite
the arbitrary nature with which blood pressure cntena are
used to diagnose hypertension, it may be the case that one
needs to possess a number of genes before his or her blood
pressure will surpass these arbitrary thresholds It may also
be the case that one needs to possess a number of genes
before addrtlonal pathologies associated with HCD (eg,
vascular damage) appear
(2) Locus heterogeneity, m which defects m dny of a number of genes or loci can confer disease suscepthhty mdependently of each other I Thus, under heterogeneity, mdlvlduals with similar phenotyplc features or disease states may
possess different genetic variants that lead to the disease
(3) Eplstasls, or gene interaction, m which the possession
of a certam mutation or genotype will confer susceptlblhty
to a degree dictated by the presence of other mutations or
genotypes Thus eplstasls reflects basic mteractlve effects of
mutations, genotypes, and/or their biologIca products
(4) Genexenvlronment interactions, m which a gene or
genes have their deletenous effects only when an mdlvldual
possessing them 15 exposed to particular environmental stirnull
(5) Developmental or hme-dependent expression of
genes, m which a gene, whether m mutant form or not, has
Its most pronounced deleterious effect at a certain time 01
developmental stage (eg, puberty) 4
Combating polygemc inheritance, heterogeneity, eplstasls, and developmental effects m gene mapping and characterization studies has been a primary motlvatmg factor
for a great deal of contemporary statlstlcal/genehc modeling and research This 15 the case because tradltlonally
such modeling and research has often focused on the “testmg” of specific (read* mdlvldual) genes or genomlc
regions, as opposed to multiple genes or envlronmental
factors, thought to influence particular traits 1 However,
although some progress m this area has been made, existmg statistIca models and methods are still inadequate and
need to accommodate an even wider array of complexltles
d they are to be at all realistic and useful 4
On reflection of the fact that blood pressure regulation
1s complex enough to admit great potential for a multitude
of genetic and nongenetic factors to induce deleterious effects, one may be forced to consider questions about how
and why mdlvlduals possessing or susceptible to such factors came to be, and how and why these mdlvlduals still
exist given the fact that they have an unhealthy and lifecompromlsmg predlsposltlon to HCD QuestIons of this
sort relate to population genetlcs theory and should be recognized as adding yet another layer of complexity to the
genetic dissectIon of HCD
Complexity
of Complex
Traits:
Populations
Standard evolutionary theory would suggest that the
emergence and maintenance of novel phenotypes m the
population at large (including diseases like hypertension
and HCD) are entirely driven by mutation and selection
That is, standard evolutionary theory would argue that
hypertension and/or HCD arose through a novel mutation
or mutations that caused elevations m blood pressure,
whereby these mutations may have, at least at some point
m the past and on the basis of their influence on other
phenotypes or traits, provided those possessmg them a survival advantage (see Julms,s J&us and Jamerson,” and
Weder and Schork,7 for a dlscusslon) Sewall Wright,
among others, challenged this very limited view by detailing the importance of stochastic (le, random) factors,
gene mteractlons, mlgratlon, population size and subdlvlslon, and mbreedmg m the emergence and mamtenance of
novel phenotypes and disease WrlghP argued that large
populations typically carry a “stockpile”
of alternative
forms of genes that would never result m or contribute to
something like a new disease or trait If not coupled with
the right environment or gene combmatlon Wright then
argued that if such a large population were to subdivide
Scho~4 Complex Cardiovascular Traits
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
(due to, eg, limited resources, social strife, or natural disasters), then the random assortment and assignment of
genes to the founders of the resulting subpopulations
might result in a greater frequency of a certain gene or
gene combination within one or a few of those subpopulations. Since these genes or gene combinations could occur with a greater frequency in a subpopulation, transmission of them to ensuing generations could result in their
greater frequency or fixation. This would be even more the
case if the subpopulation had a relatively small size initially, since the founding gene pool would be relatively
small and mating members within that subpopulation
would likely merely “reshuffle” existing genes and possibly push them toward an even greater frequency or fixation. If individuals with these stochastically determined
prevalent genes or gene combinations were more fit or had
a survival advantage in a different environment, then migration of those individuals to that different environment
would result in a set of individuals whose greater fitness
in that environment would create further propagation of
the relevant genes or gene combinations.9
Consider Fig 2 and the “1” gene variant. It is rare (relative to all the genes) in the original population, but not
as rare in the leftmost subpopulation. Such an aggregation
of “1” genes in this subpopulation may have been purely
a chance event or may have been guided by some factor
(ability to withstand a different environment). In either case,
there is now a higher probability that individuals with that
gene will mate and propagate those genes than in the parent
population. This subpopulation can undergo further division
and thereby lead to an even greater abundance of such
genes, again either by chance assortment or selection. An
allele or genetic combination may even become fixed or
lost (ie, everyone in a population has the gene or everyone
in the population does not have the gene) as a result of
random or selective forces (eg, the bottom, leftmost subpopulation of Fig 2). These genes could confer advantage
in other environments. Thus, the random assortment of
genes through population stratification may result in gene
combinations that result in the greater fitness of the individuals possessing them in environments different from the one
in which they arose. This is the substance and basis of the
“Shifting Balance of Evolution” (SBE) theory.
Wright’s arguments can easily be invoked in discussions about the complexity of HCD: Since there are so
many physiological and biochemical pathways that mediate blood pressure regulation and the human species is
relatively old, with many population subdivisions and environmental changes, there are quite likely to be, on a
worldwide scale, different mutations and gene combinations contributing to HCD. This insight is even more compelling in light of the very great environmental differences
between parts of the world. Consider the fact that HCD
can be understood as a “disease of civilization,” which
has been exacerbated or made prevalent by modern lifestyles, dietary habits, and technological advance. 10Three
basic facts contribute to this suggestion:
(1) Much HCD develops late in life, ie, after or during
the reproductive years, and thus is able to manifest itself
to a greater degree in modern society simply because life
expectancy has increased dramatically.
(2) Much HCD is associated with urbanization and
“westernized”
lifestyles and diets (eg, high-salt diets, inactivity and obesity, pollution, and stress) that were not
prevalent in the past and/or do not exist in some parts of
the world to the same degree that they exist in others.
FIG 2. Schematic
representation
of aspects
of Sewall Wright’s
“Shifting
Balance
of Evolution”
(SBE)
theory.
The large
circle denotes a large, original population,
which subdivides
into
the smaller populations
(characterized
by the smaller circles). The
numbers
within the populations
denote variant genes, either at a
single locus or over multiple loci, that influence or cause phenotypes of one sort or another either in isolation or in combination.
The numbers
encased in a small circle denote recently emerged
variants or mutations.
The different shading patterns within a population reflect different environments
(climates, terrain, food availability, etc). Dashed lines denote paths of “migration.”
(3) Palliative and curative, though not necessarily preventive, medicines for HCD (and especially hypertension) exist,
allowing individuals who otherwise might suffer or die from
HCD to exist and transmit the responsible deleterious genes
to ensuing generations. Although this phenomenon is not
likely to contribute greatly to certain forms of essential hypertension since many persons inflicted by HCD and hypertension are older and past the key reproductive years, for
other forms of HCD (eg, precocious myocardial infarction),
such a phenomenon could play a role.
Such strong environmental determinants of HCD not
only suggest the validity of concepts, like Wright’s, that
emphasize a role for the environment in directing the
emergence and maintenance of trait variation but also suggest a role for genexenvironment interaction studies in the
dissection of the genetic basis of HCD. ii.12
Methods for the Genetic Dissection of
Complex Traits
The previous two sections outlined aspects of the physiological and biochemical determinants of blood pressure regulation and evolutionary theory in an effort to put the difficulties
surrounding the genetic dissection of HCD into a context. It is
thus important to consider the question of just why current
strategies for identifying genes are ill equipped to accommodate and overcome these difficulties without modification.
There are two basic strategies for characterizing genes
that influence complex traits: candidate gene analysis and
whole-genome searches. i-3 Candidate gene analysis is
very straightforward: one merely tests the association between a particular genie variant (ie, allele) and a disease
or trait with the hope of identifying a variant that is more
frequent among individuals with the trait than those without the trait due to a causal relationship between that variant and trait. Candidate gene analyses are therefore dependent on knowledge about a gene or variant, and the
148
Hypertension
Vol29,
No I, Part 2
January 1997
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
appropriatenessof the analystsof a parttcular geneis only
as good as the knowledge that makesthe geneor variant
a “candidate” m the first place Such knowledge can be
obtained from biological insights (eg, the gene 1sknown
to be expressedm a certain tissueof relevanceto the trait
under scrutmy), homology to other genes,guesswork,or
other factors. A problem with candidategene analysis m
light of the commentsm the prevtous secttonsISthat there
are likely to be numerous(if not mnumerable)candidate
genesfor HCD Analysts of each and every one of these
candidates,m isolation of the others, may amountto testing every gene on the human genome-an endeavor
fraught with stattstrcalproblemsrelating to false-positive
results 13~4In addition, sincethere is likely to be a great
deal of heterogeneity, both with respectto the genesthat
predisposeone to HCD andthe envu-onmentsthat onemay
live m that induce suscepttbihty to HCD, finding appropriately homogenouscase and control groups (ie, nonHCD mdrvtduals) might be problematic 15Although there
are strategiesthat alleviate the control group problem,15
these strategiesdo not necessarilyallow one to test the
simultaneouseffect of multiple loci or environmental factors and thus are not necessarilyappropriatefor a comprehensive assessment
of HCD geneticsand risk factors.
Whole-genomesearchesinvolve gatheringa largenumber of related mdivtduals thought to be segregatingfor
genesthat influence a trait and then tracing the putative
parent-to-offspring cotransmissionof variants (ie, alleles
or genotypes)at landmarkspotsalongthe genome(known
as marker locr) with possrbletrait-mfluencmg variants or
alleles. If one can conclude that alleles at a particular
marker locus appearto segregate(or be transmittedalong
with) genesseeminglyinfluencing the presenceof the trait
or diseasein question, then one could infer that a gene
actually mfluencmgthe trait or disease1snear,or “linked”
to, the marker locus m question.Stattsttcal methodsused
to draw mferencesabout the putative cotransmtsstonof
marker locus allelesandtrait-influencing alleleshave been
termed “linkage analysis” methodsand have received a
great deal of recent attention.r-3There are two generalapproachesto linkage analysis.parametricpedigreeanalysts,
which mvolves tracing cosegregattonand recombmatton
phenomenabetween observed marker alleles and unobservedputative trait-influencing allelesamongmembersof
large pedigrees,and allele-sharingmethods,which assess
the number of marker allelessharedat a parttcular locus
amongpairsof relatives manifestingthe sametrait Schork
and Xui6 have consideredthe relative advantagesand dtsadvantagesof eachapproach.It shouldbe emphasizedthat
candidategenescould be assessed
within a linkage analysis framework by simply treating the alleles at the candidate geneas though they were associatedwith a marker
locus One of the biggest problemswith pedigreeand allele-sharinganalysisapproaches1sthat most of then implementattonsfocus on the detection of single loci or genetic variants (much like many candidategene analyses),
which make them somewhatunsuitedfor the analystsof
multtgemc traits like HCD In addttion, linkage strategies
are notoriously nonpowerful for detecting genes with
small to moderateeffects 14~6 Also, the collection of families necessaryfor conductmggeneticlinkage analysesand
genome-widesearchesmay require finding a large number
of families wtth individuals possessmg
the trait of interest
The use of a large number of families with different environmental exposuresand genetic or ethnic backgrounds
could introduce problems associatedwith heterogeneity,
whereby the effect of one geneis washedout by the effect
of others (te, its effect 1snot constant, detectable,or even
presentm all the mdtvtduals m the sample)1.21416
There are other issuesthat plague candidategene and
linkage analysis.Many of thesehave beendiscussedm the
literature, although they do not necessarilybear on the
complexrty of the traits to be studredbut rather on statrstical phenomena,such as marker mformattvlty, marker
spacing,and type I and type II error rates r
Directions
for Future
Research
In an effort to accommodatethe kmd of complextty
underlying HCD m candidate gene and whole-genome
searches,one nught have to consider a number of issues
Someof theseissuesare describedm tsolatton below but
have beentouched on elsewhereas well 124 14 17-n
Finding More Homogenous Populations
Sample From
to
Obvtously, one very good way to cut down on possible
heterogeneity problemsplaguing HCD genetics research
would be to samplemdtvtduals known to be of common
ongm (te, likely to possessthe sameset of mutant genes
and genetic variants predisposmgto HCD) and exposedto
common environments Such sampling has been given
heavy emphasism linkagedisequllibrmmmappingstudies,
wherethe relative tsolationof a populatton,its age,its size,
andits environmentalhomogeneityareall consideredm the
mappingeffort 20One drawback of such studiesISthat the
genesidentified may not be “ubiquitous” and may m fact
causeHCD only m the populatton studied Consider the
study of an island populattonfounded by a smallrehgtous
sect that promoted a strict lifestyle. The genesunderlying
HCD amongthis group of people may be “pnvate” alleles
that are unique to that populatton and not contribute to
(becausethey don’t exist amongpeoplewith) more “garden variety” forms of HCD seenm much larger populations Such an argument is not compellmg if one merely
wants to determinea phystologtcal mechanismthat mfluencesblood pressureby finding a gene Finding special
populattons 1snot the only way one could preserve homogeneity One could attempt to identify unique features
within personshaving a common condttton (eg, obese,
type II diabeticswith HCD) m an effort to cull out a more
clinically homogenousgroup The mottvatton for this
would be to find a group of mdtvtduals that have a condttton causedby a common setof dysfuncttonal genes111
Assessing Population
Structure
In the absenceof island populations and the like, one
could perform molecular assayswtthm a large populatton
in an effort to determine more genetically homogenous
subgroups For example, one could try to determine the
amount of admixture withm a populatton and attempt to
exploit this admixture to map genes22In addmon, one
could attempt to determine the relative genetic distance
between populationsm an effort to assesstheir possible
common origins and ultimate homogeneity or attempt to
reconstruct the genealogicalrelattonshtpsamong people
within a populatton so this information could be exploited
in genemappingefforts.2324
Making
Better Use of Animal Models
Mapping genesthat influence tractsm model organisms
can help humangenettctstsfind andcharacterizegenesthat
Schork Complex Cardiovascular Traits
influence analogous human traits m two ways First, model
organism studies have the capacity to expose systems and
subsystems influencing a trait or condition that are likely
to have human counterparts. Such knowledge can steer
human geneticists to physiological and biochemical systems whose genetic bases might be known or easily identified Second, genes are known to be conserved throughout evolution, so that finding a gene that influences blood
pressure m rats, for example, may lead one to study the
homologous human gene. Of course, the leap from rats to
humans is a large one, so that the gene identified m rats
may have lost (or changed) its function in humans
Promoting
Better Physiology
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Obviously, the greater our understanding of the phywological and biochemical determmants of blood pressure
regulation, the easier tt will be to put the roles each gene
might have mto perspective. Thus, for example, it would
be worthwhtle to map genes that mfluence traits at lower
levels of a phystological hierarchy Such genes would
likely be easier to identify since the phenotypes they mfluence are not as far removed from the genetic substrate
that determines them (or at least not to the same degree as
the more remote trait they impact). Thus, there are hkely
to be fewer genes and other factors that influence these
“intermedrate” tracts. In addition, the knowledge gamed
from the identification of such genes would shed enormous
light on how the determmants of, eg, blood pressure regulation, interact and operate when upset or dysfunctional
Note that such mformatton can be gleaned from pharmacological probes and studies as well.4.25
Better Statistical Methods and Designs
The development of linkage and candidate gene strategies that can accommodate multiple genetic and envnonmental factors should easily advance HCD genetics research In addition, more efficient designs for mapping
genes can only result in a greater number of research efforts, leading to a possible convergence and corroboration
of results Just how such designs would take their shape is
of course m question, but recent work by Risch and others
suggest some directions. 14.26Such designs may also be dictated by technological breakthroughs. For instance, tf sequencmg genes becomes cheap, then study designs and
analytical methods for directly relating sequence vartation
and trait variation will likely become focal points m statistical genetics research
Conclusions
The emphasis among current medtcal researchers on the
genetic dtssection of complex traits such as HCD will not
likely dimmtsh any time soon The difficulttes surroundmg
the full disclosure of the array of genetic and environmental determinants of HCD, many of which have been
touched on m this paper, will likely drive relevant research
well mto the future. The direction such research will take
will likely be vastly different from current research paradigms For example, some have argued that the “future”
of complex genetic trait research will be of a largely statistical orientation 14 This is highly unlikely, since the
development of better animal models, m vitro assays,
pharmacological probes, gene expression analyses, and
population genetic mvestigations will likely overshadow
discusnons about which statistic or modeling device will
149
be the least error prone. This does not, however, undermme the significance quantttattve methods will have m
HCD research Ultimately, what would seem to be the
most compelling position to take in this light is the simple
promotion of concerted efforts to integrate various strategies and the knowledge obtained with them 19~~7
References
1 Lander
2
3
4
5
6
11
12
13
14
15
16
17
18
ES, Schork NJ Genettc dtssectton of complex tracts Scrence
1994,265 2037-2048
Schork N, Chakravartt
A A nonmathematical
overview of modern
gene mappmg techniques apphed to human dtseases In Mocknn S,
ed Molecular
Genettcs
and Gene Therapy
of Cardwvascular
Duease New York NY Marcel Dekker Inc, 1996 79-109
Weeks DE, Lathrop GM Polygemc dtsease methods for mappmg
complex dtsease traits Trends Gener
1995,ll 513-519
Schork NJ, Nath SP, Lmdpamtner
K, Jacob HJ Extenstons of quanbtattve trait locus mappmg m experimental
organisms Hyperrenston
1996 In press
Juhus S The defense reaction a common denominator of coronary
risk and blood pressure m neurogemc hypertension?
Clrn Exp Hypertens.
1995,17 375-386
Juhus S, Jamerson K Sympathetics,
msulm resistance and coronary
nsk m hypertension
the ‘chicken-and-egg’
question J Hyperrens
1994.12 495-502
Weder AB, Schork NJ Adaptation, allometry, and hypertension
Hypertensmn
1994.24 145-156
Wright
S Evolutton
m Mendehan
populations
Genefrcs
1931.16 97-159
Wright S The shtftmg balance of evolution theory and macroevolutron Annu Rev Genet 1982;16 l-19
Boyd-Eaton
S, Konner M, Shostak M Stone-agers m the fast lane
chrome degenerattve diseases m evoluttonary
perspective Am J Med
1988,84*739-749
Khoury MJ, Adams MJ, Flanders WD An epidemrologtcal
approach
to ecogenettcs Am J Hum Genet 1988,42
89-95
Ottman R Gene-environment
interaction and public health Am J
Hum Genet
1995.56 821-823
Lander E, Kruglyak L Genettc dissectton of complex tracts gmdelines for mterpretmg
and reporting
hnkage results Naf Gener
1995.11 241-247
Risch N, Mertkangas
K The future of genetic studtes of complex
human dmeases Science 1996,273 1516-1517
Spellman RC, McGmms RE, Ewens WJ Transmtsston test for hnkage dtseqmhbnum
the msuhn gene region and msuhn dependent
diabetes melhtus (IDDM)
Am J Hum Genet
1993,52 506-516
Schork NJ, Xu X Srbpatrs versus pedrgrees what are the advantages?
Dmbefes
Rev 1996 In press
Ghosh S, Schork NJ Genetic Analysts of NIDDM
the study of quantttative traits Diabetes
1996,45 I-14
Ghosh S, Colhns FS The geneticist’s approach to complex disease
Annu
Rev Med.
19 Thlbbomer
Genet
Dev
1996,47
M, Schork
1995.5
333-353
NJ The genetics of hypertension
Curr
0pm
362-370
20 Jorde LB Linkage diseqtuhbrmm
as a gene-mapping
tool Am J Hum
Genet 1995.56 11-14
21 Xu X, Schork NJ Lmkmg genes and environmental exposure why China
presents special opportunmes Cancer Causes Control
1996 In press
22 Stephens J, Bnscoe D, O’Brien S Mapping by admixture
hnkage
dtseqmhbrmm
m human populations
hmtts and gmdelmes Am J
Hum Genet
1994,55 809-824
23 Gmns EI, Ott J, Egeland JA, Allen CR, Fann CS, Pauls DL, Wetssenbach .I, Carulh JP, Falls KM, Ketth TP, Paul SM A genome-wide
search for chromosomal
loci lmked to btoolar affective disorder m
the Old Order Amish Nar Genet 1996,12 431-435
24 Freimer NB. Reus VI, Escanulla MA, McInnes LA, Spesny M, Leon
P, Service SK, Snuth LB, Sdva S, RoJas E, Gallegos A;Meia L, Fourmer E, Baharloo S, Blankenshrp K, Tyler DJ, Batkt S, Vmogradov
S,
Wetssenbach J. Barondes SH. Sandkuul LA Genetlc mapoma usmu
haplotype, association and linkage methods suggests a lo&fo;sever~
bipolar dtsorder (BPI) at 18q22-q23 Nat Gener 1996,12 436-441
25 Schork NJ, Weder AB The-usebf genetic mformatton
in large-scale
clnucal trials applications to Alzhetmer’s disease Alzhecmer
DwAssot Dtsord
1996.10 22-26
26 Rtsch N, Zhang H Extreme discordant sib pairs for mapping quantitattve trait loct m humans Sctence
1995,268 1584-1589
27 Herrera VLM, Rum-Opazo
N Genettcs of hypertension
a multidtsclplmary challenge Trends Cardrovasc
Med
1991.1 185-189
Genetically Complex Cardiovascular Traits: Origins, Problems, and Potential Solutions
Nicholas J. Schork
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Hypertension. 1997;29:145-149
doi: 10.1161/01.HYP.29.1.145
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1997 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://hyper.ahajournals.org/content/29/1/145
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally
published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not
the Editorial Office. Once the online version of the published article for which permission is being requested
is located, click Request Permissions in the middle column of the Web page under Services. Further
information about this process is available in thePermissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Hypertension is online at:
http://hyper.ahajournals.org//subscriptions/