Applying Genomics to the Study of Complex

Disease
Brian D. Juran, B.S.,1 and Konstantinos N. Lazaridis, M.D.1

ABSTRACT

The interest in dissecting the genetic and environmental components of complex

human disease is growing, fueled by the emerging advances in the field of genomics and
related disciplines. Improved understanding of the pathogenesis of complex liver diseases
such as gallbladder stones, nonalcoholic fatty liver disease, viral hepatitis, and hepatocel-
lular carcinoma remains a goal of the clinical and experimental hepatologist alike. Despite
the scientific progress and technological advancement, elucidating the underlying mech-
anisms of complex hepatic diseases from the genomic standpoint will be demanding.
Complexity of genomic structure and function, disease heterogeneity, influence of the
environment on disease development and progression, and epigenetics all contribute to the
challenge. To overcome these obstacles, novel conceptual frameworks regarding biological
systems and human diseases are necessary in addition to a coordinated endeavor among
different scientific disciplines. Deciphering in an integrated fashion the genomic, tran-
scriptional, and translational aspects of the pathogenesis of complex liver diseases will lead
to their better prediction, diagnostics, and treatment.

KEYWORDS: Systems biology, disease susceptibility, genetics

C omplex diseases are heterogeneous, the cumu-
lative result of a wide array of gene variants (both
common and rare), somatic mutations, epigenetic mod-
ifications, and environmental exposures, the combina-
tions of which are apt to be significantly varied among
the spectrum of affected individuals.1 Thus, inherited
genetic variation is not directly the cause of complex
disease but instead acts to mediate the risk of disease
development in response to environmental exposures.
The clinical and genetic heterogeneity inherent in these
disorders greatly complicates our ability to dissect the
underpinnings of their etiology and pathogenesis.
In the following pages we provide a brief overview
of the concepts involved with disease complexity and the
field of genomics. We then discuss the current strategies
and future challenges of applying genomics-based stud-
ies toward achieving a better understanding of complex
disease.
DISEASE COMPLEXITY
Systems Biology: Robustness, Modularity,
and Redundancy
We humans are in essence complex biological machines,
shaped over millennia by evolutionary forces and defined
by our genome. All of the information necessary for life
is encoded in our DNA. However, its utilization is
dependent on the cellular context in which it resides,
allowing the development, organization, and sustain-
ment of the diverse set of cells that comprise us. The
ability of the genome to generate and coordinate this

1
Division of Gastroenterology and Hepatology, Center for Basic
Research in Digestive Diseases, Mayo Clinic College of Medicine,
Rochester, Minnesota.
Address for correspondence and reprint requests: Konstantinos N.
Lazaridis, M.D., Mayo Clinic College of Medicine, 200 First Street
SW, Rochester, MN 55905.
Genetics and Genomics of Complex Diseases in Hepatology; Guest
Editor, Konstantinos N. Lazaridis, M.D.
Semin Liver Dis 2007;27:3–12. Copyright # 2007 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
USA. Tel: +1(212) 584-4662.
DOI 10.1055/s-2006-960167. ISSN 0272-8087.
3
4 SEMINARS IN LIVER DISEASE/VOLUME 27, NUMBER 1 2007

tremendous level of diversity has evolved over the billions
of years that DNA-based life has existed.2,3 Robustness is
the driving force behind this process and is a fundamental
feature of complex biological systems.4 Simply put, robust
properties provide phenotypic stability in the presence of
unpredictable environmental or genetic challenges. Com-
plex systems become robust through modularity and
redundancy, both of which act to mitigate the potential
for system-wide damage.5 Modular structure is pervasive
in life and often exists in a hierarchy (i.e., organs, tissues,
cells, and organelles). In addition to physical structure,
functional and regulatory mechanisms such as metabo-
lism, cell cycle, and signal transduction are widely modu-
larized, taking the form of numerous networks and
pathways operating at the postgenome level.5,6 Intercon-
nection of these networks and widespread gene duplica-
tion derive the means for use of alternative genes or
pathways generating redundancy,7 a compensatory proc-
ess to achieve the desired phenotype when failure in
another gene or module occurs (Fig. 1). Thus, redun-
dancy can and often does generate disconnect between
genotype and phenotype, a process that is dependent on
higher order pathway and network interactions and the
context in which the genome is utilized.8,9 These funda-
mental features of complex biological systems signifi-
cantly affect the genetic mechanisms underlying the
etiology of complex human disease and pose limits on
our current ability to study them.
Disease Genetics
Genetic predisposition is thought to play a role in most
human diseases.10 Currently, three classifications based
on genetic involvement with disease are recognized:
chromosomal, Mendelian, and complex.11 Chromosomal
disorders are characterized by gross abnormalities in
chromosome number or structure and often result in
preterm death related to developmental abnormalities.

Figure 1 Interconnected biological pathways generate redundancy. The interrelation of numerous pathways generates a redundant
network, buffering the effect of input variability and genetic polymorphism on phenotype. Shown is a simplified hypothetical signaling
network through which phenotypic effects are stimulated by a primary input that is detected by members of two distinct modular
pathways (delineated by boxes). In this example, these pathways communicate through a primary node (dark gray square) that acts to
mediate a large portion of the signal in the network and provides a feedback loop to diminish the effect of input variation on the
phenotype (illustrated by dotted lines). However, some of the signal from each pathway, as well as a secondary input (dark gray circle), is
able to bypass this node and directly stimulate an effect on phenotype. Genetic polymorphism in individual components of the network
(i.e., genes) is unlikely to have a great effect on phenotype because of the many means through which the input stimulus can be passed.
However, a slight phenotypic effect could be demonstrated by these putative variants, potentially contributing to risk of disease.
Furthermore, genetic variants of the primary node and secondary nodes (light gray circles) are more likely to display a detectable effect.
 APPLYING GENOMICS TO THE STUDY OF COMPLEX DISEASE/JURAN, LAZARIDIS 5

Mendelian diseases run in families and display classic
patterns of inheritance, such as autosomal dominant,
autosomal recessive, or X-linked. In general, these
disorders are rare, arise early in life, and can be attributed
to mutation in a single gene that, when present, directly
causes the disease phenotype. Often these causative
mutations are family specific.
The vast majority of human diseases are genet-
ically complex, wherein the direct correspondence be-
tween causative genotype and disease phenotype
characteristic of Mendelian disorders is not present.12
Instead, complex diseases develop as the cumulative
result of environmental exposures, exerting their effect
over time, in genetically susceptible individuals. There-
fore, the genotypic components of complex diseases are
not causative but rather mediate disease risk. Many such
susceptibility genotypes are expected for each complex
disorder, some of which are common to similar diseases
(e.g., autoimmune disorders) and some of which may be
disease specific. Regardless, the individual contributing
variants are likely to have only a slight contribution to
the overall risk of each specific disease in the affected
population (Fig. 2).
Complex diseases are diverse in clinical presenta-
tion, progression, and response to treatment. Because of
this heterogeneity, it is useful to break down complex
disorders to a series of disease traits or phenotypes for
consideration in genomic studies. These traits can be
qualitative, such as the presence of a comorbid disease, an
associated diagnostic marker, or a previously determined
risk factor. In addition, these traits could be quantitative
measures such as age of disease onset, results of serum
liver tests, or gene expression profiles. Comprehensive
characterization, assessment, and utilization of these
traits will be essential in the dissection of the genetic
and environmental contributors to complex disease.
Disease concordance in monozygotic (MZ) twins
is presently the best means for establishing the strength
of the inherited genetic determinates of complex dis-
ease.13 As MZ twins have identical DNA sequences,
disease concordance is suggestive of genetic influence,
whereas discordance indicates a greater role for environ-
mental or stochastic effects. Furthermore, the difference
in disease concordance between MZ and dizygotic (DZ)
twin pairs may provide additional insight into the
mechanisms at play in complex disease development.
For example, large differences in disease concordance
between MZ and DZ twin pairs could signify the
involvement of numerous risk-modifying gene variants
and, conversely, slight differences in concordance might
imply a stronger shared-environment effect. However, it
should be noted that de novo genetic and/or epigenetic
effects prior to or after MZ twinning could have an effect
on MZ disease concordance and MZ/DZ concordance
ratios, obscuring the reality of the inherited genetic
contribution to disease.14 Familial aggregation also
provides a way to estimate the genetic impact on
complex diseases,11 as family members share more
genetic material between themselves than with the
general population. Relative risk ratios (l) are often
used to illustrate the risk of disease development in the
families of affected individuals. The l is calculated by
dividing the prevalence of a complex disease among
family members (often specifically siblings, ls) by the
prevalence of the disease in the population at large.11 In
general, higher l values suggest a greater role of the
genetic component in disease.
GENOMICS
From the earliest stages of life the human genome is
selectively activated in response to both internal and

Figure 2 Comparison between Mendelian and complex diseases. In general, Mendelian diseases have lower frequency in the
population, display higher prevalence, and are caused by a single or a few genes, each of which has a high effect on the disease
phenotype. In contrast, complex diseases are usually more common, have reduced prevalence, and are mediated by several to
numerous genes, each of which has a small contribution to the phenotype.
6 SEMINARS IN LIVER DISEASE/VOLUME 27, NUMBER 1 2007
external cues to guide the development and continued
function of numerous cell types organized into higher
order structures such as our tissues and organ systems.
Genomics is the field of study that seeks to understand
and characterize the genome’s role in this process. The
achievement of sequencing the human genome is in-
deed momentous and has provided new impetus to the
study of its involvement in disease pathogenesis. How-
ever, the intricacies of genomic function cannot be
understood by solely focusing on our species. To this
extent, the genomes of a wide variety of organisms
ranging from bacteria to mammals have been eluci-
dated, and the effort continues. Complete lists of these
genome sequencing projects are freely available through
the National Center for Biotechnology Informa-
tion (NCBI) website (http://www.ncbi.nlm.nih.gov/
entrez/query.fcgi?db=genomeprj).
Sequence Variation
The sequence of the human genome is varied, as
illustrated by the nearly 12 million polymorphisms
currently cataloged on the NCBI’s dbSNP website
(http://www.ncbi.nlm.nih.gov/SNP/). Single nucleo-
tide polymorphisms (SNPs) are the most prevalent of
these variants, accounting for over 90% of human
polymorphic loci.15 Distribution of SNPs across the
genome is rather uniform and primarily dependent on
the frequency of the minor allele (MAF). For instance,
a SNP with a MAF of 1% is expected to be present in
every 300 bases of genomic DNA, whereas a SNP with
MAF of 40% is expected in only every 3300 bases.16
Resequencing portions of the genome in 137 individ-
uals has confirmed that SNPs are quite common,
occurring approximately every 180 base pairs.17 In
addition, a majority of these SNPs (64%) are rare,
with MAF < 5%.17
The location of a SNP, to some extent, suggests
its potential for functional significance and impact on
disease risk.18 SNPs in gene coding sequence resulting
in premature termination (i.e., nonsense SNPs) or
amino acid substitution (i.e., nonsynonymous SNPs)
alter protein sequence and possibly function and, there-
fore, are more likely to demonstrate a phenotypic effect.
Interestingly, resequencing of two genes in a large
reference sample of 450 individuals identified a large
number of rare nonsynonymous SNPs that were not
detected in a smaller screening set,19 suggesting that
many SNPs with a high likelihood to affect phenotype
(and by correlate disease) are present in the population,
albeit at low prevalence. SNPs located in splice site
recognition, transcription factor binding, or enhancer
sequences also have the potential to alter phenotype by
affecting gene expression, splicing, or stability. How-
ever, we are not yet able to predict these functional
consequences a priori. SNPs located between genes
(i.e., intergenic SNPs) are thought to be far less likely
to affect function. Nevertheless, it has been suggested
that a large portion of this intergenic sequence is under
positive selection and, thus, potentially functional.20 To
facilitate a better understanding of genome operation,
the National Human Genome Research Institute
(NHGRI) has launched the ENCODE (ENCyclope-
dia of DNA Elements) program, which seeks to per-
form an exhaustive determination of all functional
elements in the human genome. Information regard-
ing ENCODE can be found on the web at http://
www.genome.gov/10005107.
Genomic Diversity
Diversity of the genome is primarily driven by random
mating and meiotic recombination, the phenomenon
during which regions between pairs of equivalent chro-
mosomes are exchanged in the course of gametogenesis,
generating discreet genetic differences between parents
and offspring.21 As we have transmitted the genetic
material through relatively few generations since our
ancestral origins, contemporary chromosomes have re-
gions of variation in common, or display linkage dis-
equilibrium (LD) (Fig. 3). Thus, the relatively young
age of our species limits the diversity of the human
genome.
The pattern of LD across the genome is incon-
sistent because of the presence of recombination hot
spots, regions of the genome in which recombination
occurs more readily.22,23 The result is that regions of low
LD flank regions of high LD, creating haplotype
blocks.23,24 Limited allelic diversity within these blocks
can potentially simplify genomic studies aimed at deci-
phering the mechanisms of complex disease.25,26 To
facilitate such efforts, the International Human Haplo-
type Map (HapMap) project (http://www.hapmap.org/)
was initiated to determine the structure of human
haplotype blocks and identify SNPs that are predictive
for the variation in a larger set (i.e., tag SNPs). To date,
the HapMap project has assessed some 3 million SNPs
in 269 individuals from four racial/ethnic groups. The
HapMap effort has confirmed that significant redun-
dancy exists among common SNPs such that local
genomic variation can be reliably determined using a
subset of tagging SNPs.22,27
The Horizon
Genome sequencing projects, variant cataloging, and
haplotype block mapping efforts all provide a solid
basis for the study of genomics but together amount to
only the ‘‘tip of the iceberg’’ in the level of under-
standing that will be required if genomic studies are to
affect globally the way in which we approach the
diagnosis, prognosis, and treatment of complex disease.
 APPLYING GENOMICS TO THE STUDY OF COMPLEX DISEASE/JURAN, LAZARIDIS 7

Figure 3 Linkage disequilibrium (LD) limits the diversity of the human genome. LD is the nonrandom association of alleles at two or
more loci. In humans, this is largely driven by the limited number of generations, and thus recombination events, through which the
genome has passed since our common ancestors, generating allele combinations that are widely shared among contemporary humans
(i.e., common haplotypes). Patterns of LD are influenced by population structure and dynamics, such as founder effects and population
admixture, and as a result display differences between racial and ethnic groups.

Increasing our knowledge regarding sequence func-
tionality, currently the aim of the ENCODE program,
will take us one step further in this endeavor by
providing a basis for the prediction of variant-induced
consequences outside the nonsense and nonsynony-
mous polymorphisms for which this approach is cur-
rently feasible. Elucidation of the rules governing
contextual genome utilization, including the genera-
tion of cell type–specific transcriptomes and proteomes
(i.e., all gene transcripts and functional proteins) as
well as the principles determining postgenome protein
network, environmental, and physiological interac-
tions, will be required before genomic effects on
high-order structure and redundant processes will be
fully appreciated.
APPLYING GENOMICS TO THE STUDY
OF COMPLEX DISEASE
The knowledge gained from our current efforts at
sequencing and cataloging the variation of the human
genome provides a sound basis for exploring its role in
modulating traits of complex disease. Admittedly, we are
ill equipped to study the effects of inherited genetic
variation across numerous physically separated loci and
determine how these combinations of alleles interact
with the environment and lead to the development of
complex disease.28 However, utilizing the genomic ap-
proaches described in the following pages, we are begin-
ning to identify simple associations between genetic
variants and complex disease traits.
Common single-variant and haplotypic associ-
ations are expected to be weak (e.g., odds ratio [OR]
< 2.0) and, thus, poor predictors of disease develop-
ment,29 but they may account for a large portion of
the disease risk experienced by the affected popula-
tion. Conversely, rare genetic variants significantly
increasing susceptibility to disease development (e.g.,
OR > 5.0) may be widespread but individually are
likely to account for disease predisposition in only a
small subset of the affected population. Moreover, the
role of emergent genetic phenomena such as somatic
mutation and epigenetic modification in complex
disease development is becoming more appreciated.
At present, it is unclear which mechanisms will prove
to have the greater overall impact on disease in
8 SEMINARS IN LIVER DISEASE/VOLUME 27, NUMBER 1 2007
general, although it is becoming apparent that all are
likely to play a role in the spectrum of most complex
disorders.
Investigating Inherited Disease Susceptibility
LINKAGE
Genetic linkage analysis seeks to identify the cosegre-
gation of polymorphic genetic markers in affected
family members to map disease-related genomic loci
by exploiting the nature of meiotic recombination.
That is, genes near each other will be inherited
together more often than those located farther apart.
Accordingly, the genetic markers segregating with the
disease are assumed to be located near (linked to) the
causative gene. The loci identified by traditional ge-
nome-wide linkage approaches have often been large
(5 to 10 Mb) because of historically applied low marker
densities and to some extent the limited number of
observable meioses in family groups,30 generally re-
quiring an extensive fine-mapping effort to pinpoint
the offending alleles. However, significantly better
resolution could be achieved in many studies by utiliz-
ing higher densities of genetic markers (e.g., SNPs), a
proposition that is becoming more affordable as the
cost of genotyping continues to drop. Both model-
based (i.e., parametric) and model-free (i.e., nonpara-
metric) linkage approaches can be employed in the
search for disease-related alleles.31 Parametric linkage
analysis calls for the researcher to specify a model of
inheritance and estimate the frequency and penetrance
of the disease genes, and it is a powerful approach
when applied to extended pedigrees with many affected
individuals. Nonparametric linkage analysis is less
powerful but does not require the specification of a
genetic model and instead looks simply for excessive
sharing of alleles identical by descent among affected
family members.
The tenets underlying linkage analysis make
this a powerful approach for the identification of
genes involved with Mendelian diseases but limit its
application to complex disorders.31 Clinical, locus,
and allelic heterogeneities, all of which are common
features of complex diseases, effectively dilute the
linkage signal, significantly reducing the chance of
identifying plausible candidate regions. Parametric
approaches are impractical, as models of inheritance
and estimations of the frequency and penetrance of
the disease genes are not readily assumable for com-
plex disorders. Moreover, the late age of onset of
most complex diseases often precludes the assessment
of multiple generations, significantly reducing the
power of both parametric and nonparametric ap-
proaches. However, the use of linkage analysis to
identify genes involved in the development of com-
plex disease could prove useful, especially when ap-
plied to families in whom the genetic component is
likely to be enriched, such as those with an unusually
high rate of disease occurrence or exceptionally early
age of disease onset. Although these families might
not be representative of the disease in the majority of
the population, findings could implicate major net-
works or pathways involved in the disease and would
certainly provide a basis for further investigations.
ASSOCIATION
In general, association studies look for a statistical
difference in the frequency of alleles between affected
and unaffected individuals. Often this involves pop-
ulation-based comparisons between cases and unre-
lated controls; however, family-based tests of
association can also be quite useful.32 Association
studies take advantage of the LD generated by meiotic
recombination throughout our ancestral history to
identify genomic loci contributing to disease pheno-
type, in contrast to linkage approaches, which observe
only recent meioses in family groups. The former
approach has traditionally been applied to the study
of genetic variants in candidate genes preselected for
their potential involvement in specific disease proc-
esses such as genes or loci identified by prior whole-
genome linkage scans or known to be involved
biochemically with disease. Lately, genome-wide asso-
ciation studies utilizing hundreds of thousands to
millions of SNPs spread across the genome have
become reality.33,34
Overall, association studies are capable of identi-
fying substantial genetic effects (i.e., OR > 2.0) on dis-
ease phenotype with relatively small sample sizes (n
!200)35 and have high power to detect small effects of
genetic variation (i.e., OR < 2.0) but require the sample
sizes to be quite large (n ! 1000). SNPs are the genotyp-
ing markers most often employed in association studies
as they are quite abundant and easy to type. Depending
on the individual marker being tested, detected associ-
ations could directly affect the phenotype (i.e., suscept-
ibility variant) or may be in LD with the true phenotypic
effector.36 In general, follow-up functional studies aimed
at explaining the disease mechanism underlying any
detected associations would be beneficial. However,
such studies are often not performed because of lack of
a suitable model system and/or adequate specimens from
which to derive RNA or protein. Moreover, when they
are performed, the results can be unsatisfying and
difficult to interpret, as the contextual milieu in which
function is affected and contributes to disease is likely to
be altered or lost.
Population-based association studies are suscep-
tible to false positive findings related to population
stratification, a phenomenon stemming from unequal
genetic backgrounds (i.e., allele frequencies) between the
 APPLYING GENOMICS TO THE STUDY OF COMPLEX DISEASE/JURAN, LAZARIDIS
case and control populations. In fact, loci completely
unlinked to the tested disease will exhibit association
when the allele frequencies in the populations are con-
siderably different.37 Moreover, less extreme manifesta-
tions of selection bias can work to cloud the results of
association studies. For example, control populations
derived from blood-bank donors may not be representa-
tive of the case population as blood donors tend to be
rigorously screened and possibly in better general health
than the cases, especially when collected for elderly
populations.38 Thus, positive associations may reflect
genetic variations involved with overall health and not
specifically the disease of interest. Another source of
false positive findings in association studies is multiple
testing. For instance, when P values of .05 are considered
significant, 1 out of 20 positive associations are likely to
be false. When extrapolated to thousands of tests,
numerous false associations are likely to be detected.
Several methods to correct for multiple testing have been
employed, but many of these are quite draconian and
probably drive the exclusion of true positive findings.39
Replication in an independent data set is the best
method to verify the research findings, and great care
should be taken to ensure that the follow-up study is
adequately powered and the controls are well matched.40
On the other hand, family-based association tests are not
prone to stratification biases and, thus, offer an alter-
native to study and confirm the observations of case-
control studies.41
Genotyping and statistical methods keep im-
proving, and LD-based association studies will con-
tinue to demonstrate usefulness in the future. The
collection of large sets of cases, their family members,
and well-matched controls remains the primary chal-
lenge to the investigator wishing to study complex
disorders. To this extent, the case for developing a large
United States prospective cohort of !200,000 individ-
uals to study the role of genes and environment in
disease development has been raised42 and is currently
debated between scientists, policy makers, and the
federal government.
Gene Resequencing
In general, association-based approaches to the identi-
fication of alleles involved with complex disease are not
well suited to identify rare, recently arising variants that
may be involved with disease risk or protection, as these
variants are not likely to be directly assessed or indirectly
detected by haplotypic association. An approach to
identifying such rare variants is the complete resequenc-
ing of a particularly interesting candidate gene/gene-
region in affected patients, most likely focused on the
protein coding exons and splice junctions, although
potentially across whole genes or multigene regions
when relatively small. This approach has been used to
9
confirm the role of leptin (the cause of extreme obesity in
the obese ob/ob mouse model) genetic polymorphism in
human obesity43 and also used in the identification of a
chemokine receptor (CCR5-delta 32) mutation that is
protective against human immunodeficiency virus (HIV)
infection and progression.44 As genotyping costs con-
tinue to decline, gene resequencing will become a more
attractive approach to the identification of the genetic
determinants of complex diseases and their phenotypes
as it allows the simultaneous assessment of both com-
mon and rare variants. Toward this end, the NHGRI is
aggressively funding the advancement of revolutionary
genome sequencing technologies, with the goal of re-
sequencing the entire human genome for $1000 (some
four orders of magnitude less than currently feasible).
When this lofty goal becomes reality, the way in which
we view and approach genome science will be forever
changed.
Investigating Emergent Disease Susceptibility:
Epigenetics, Somatic Mutation, and Aging
Although inherited genetic variation is likely to play a
significant role in determining susceptibility to complex
diseases, it is becoming apparent that epigenetic changes
and mutation in somatic cells may contribute a greater
role in the etiology of these disorders than previously
thought.14,45 This has become widely apparent in cancer,
where some level of inherited risk is seemingly present,
but the mechanisms leading to malignant transformation
primarily involve misregulated epigenetics and accumu-
lation of somatic mutation.46 The extent of these epi-
genetic and mutagenic phenomena is possibly somewhat
determined by inherited variation, invoking a vicious
cycle, but they are thought to be largely driven by
stochastic phenomena and aging.
Epigenetics involves stable changes in gene ex-
pression that do not entail alteration of DNA sequence
and are decoupled from labile, reactionary transcrip-
tional control processes.14 This form of transcriptional
regulation is known to involve the methylation of
cytosine bases at cytosine-guanine dinucleotides but
may involve some of the classes of noncoding RNAs as
well.14 Epigenetic events play a major role in mamma-
lian development and in the maintenance of tissue-
specific cellular function, and aberrant methylation is
becoming increasingly evident in the expression of
disease phenotypes.14,46 However, the methylation
profile of the human genome remains largely un-
known. To this extent, the Human Epigenome Project
has been established, which aims to analyze DNA
methylation patterns in the regulatory regions of all
known human genes in most of the major cell types in
a healthy state and their diseased counterparts.47 In-
formation regarding the current status of this effort
can be found at http://www.epigenome.org.
10 SEMINARS IN LIVER DISEASE/VOLUME 27, NUMBER 1 2007
Somatic mutations ranging from individual point
mutations to large rearrangements, duplications, or de-
letions are increasingly noted as playing a role in the
development of complex diseases, primarily in cancers
for which diseased tissue (i.e., tumor) is often observable.
DNA rearrangements or deletion resulting in the loss of
heterozygosity (LOH) at one allele can unmask the
deleterious effect of a recessive-acting mutation in a
tumor suppressor gene and lead to the development of
malignancy.48 LOH is identified when heterozygosity
for a genetic marker is noted in the germline DNA but
not in the DNA of the tumor. DNA rearrangements can
also generate fusion genes, sometimes resulting in a
gain-of-function abnormal hybrid protein. Previously
identified fusion genes have often been classified as
oncogenes because of their involvement with malignancy
and poor outcome; one example is BCR-ABL, which is
strongly associated with the development of chronic
myeloid leukemia.49 Moreover, segmental gene duplica-
tion, occurring by a process involving low-copy repeat
sequences, can affect gene copy number and, therefore,
dosage of gene product, which can ultimately have an
effect on phenotype. Such copy number changes have
been associated with susceptibility to HIV infection.50
At present, the extent to which somatic mutation may
play a role in complex disease phenotype is unclear.
Moreover, this putative effect is hard to assess.
Finally, some portion of most common complex
disease cases may be attributed solely to stochastic
processes related to aging, primarily the result of accu-
mulated somatic mutation and cellular damage due to
long-term exposure to harmful endogenous and environ-
mental agents.51,52
CHALLENGES
Presently, we stand in the midst of scientific promise and
challenges of applying genomics to the study of complex
disease. Ideally, these obstacles can turn into opportu-
nities leading to discovery of better methods for disease
prognosis and novel therapies. Because of the Human
Genome Project and subsequent initiatives (e.g., Hap-
Map, ENCODE), we are now able to read the instruc-
tion of our genome and we possess the first tools to begin
elucidating its functionality. However, we still lack
methods to systematically examine the interactions
among the numerous genes of the genome as well as to
comprehend how variation can leave some of us more
vulnerable to developing disease than others.
The barriers we have to overcome in genomic
research are considerable. First, it is important to realize
the intricate nature of human biological systems. Clearer
understanding of the redundancy of networked arrange-
ments is needed in the context of the genome itself and the
high-order processes it encodes. Second, we lack the large
patient, family member, and matched control specimen
banks needed to gather comprehensive data sets on
genomic variation and environmental exposures. Third,
the definition and classification of several complex dis-
eases and associated traits, whether clinical, biochemical,
or other, have to be expanded and improved to minimize
disease heterogeneity.
Pursuing clinical genomic research requires di-
verse expertise of investigators (i.e., clinicians, labora-
tory-based researchers, genetic epidemiologists,
statistical geneticists, bioinformatics specialists). This
need comes in antithesis to the conventional model of
research programs where an individual principal inves-
tigator is responsible for the direction of the study. The
cost of current genomic-based technology methods is
falling but still quite high, limiting the application of
these exciting approaches to large, well-funded research
programs. Improvements of high-throughput solutions
are necessary to reduce the price tag of these technologies
and make them affordable to more researchers and
applicable across the spectrum of complex diseases.
Finally, but most important, the protection of human
participants, whether patients, unaffected family mem-
bers, or unrelated healthy controls, has to be ensured.
These individuals are the key component of genomic
research and their legal rights need to be protected if we
wish to continue on with genomic science and to
eventually apply genomic-based medicine for the good
of humankind.
CONCLUSIONS
Genomics offers the potential to change the way we
diagnose and treat complex disease. The foremost goals
of medical research are to advance the prognostication of
disease and to develop safe, effective novel drugs. A
clearer understanding of the roles the genome as a whole
and environmental interaction play in complex disease
pathogenesis will provide the keystone for future medical
breakthroughs.
ACKNOWLEDGMENTS
Supported by NIH grant DK68290, the Palumbo Foun-
dation, and the Morgan Foundation. The authors thank
Stacy Roberson for secretarial assistance.
ABBREVIATIONS
DZ dizygotic
HIV human immunodeficiency virus
LD linkage disequilibrium
LOH loss of heterozygosity
MAF minor allele frequency
MZ monozygotic
NHGRI National Human Genome Research
Institute
 APPLYING GENOMICS TO THE STUDY OF COMPLEX DISEASE/JURAN, LAZARIDIS
OR odds ratio
SNP single nucleotide polymorphism
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