Applying Genomics to the Study of ComplexDisease

Brian D. Juran, B.S.,

and Konstantinos N. Lazaridis, M.D.

ABSTRACT

The interest in dissecting the genetic and environmental components of complexhuman disease is growing, fueled by the emerging advances in the field of genomics andrelated disciplines. Improved understanding of the pathogenesis of complex liver diseasessuch as gallbladder stones, nonalcoholic fatty liver disease, viral hepatitis, and hepatocel-lular carcinoma remains a goal of the clinical and experimental hepatologist alike. Despitethe 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 theenvironment on disease development and progression, and epigenetics all contribute to thechallenge. To overcome these obstacles, novel conceptual frameworks regarding biologicalsystems and human diseases are necessary in addition to a coordinated endeavor amongdifferent scientific disciplines. Deciphering in an integrated fashion the genomic, tran-scriptional, and translational aspects of the pathogenesis of complex liver diseases will leadto their better prediction, diagnostics, and treatment.

KEYWORDS:

Systems biology, disease susceptibility, genetics

omplex diseases are heterogeneous, the cumu-lative result of a wide array of gene variants (bothcommon and rare), somatic mutations, epigenetic mod-iﬁcations, and environmental exposures, the combina-tions of which are apt to be signiﬁcantly varied amongthe spectrum of affected individuals.

Thus, inheritedgenetic variation is not directly the cause of complexdisease but instead acts to mediate the risk of diseasedevelopment in response to environmental exposures. The clinical and genetic heterogeneity inherent in thesedisorders greatly complicates our ability to dissect theunderpinnings of their etiology and pathogenesis.In the following pages we provide a brief overview of the concepts involved with disease complexity and theﬁeld of genomics. We then discuss the current strategiesand future challenges of applying genomics-based stud-ies toward achieving a better understanding of complexdisease.

DISEASE COMPLEXITY

Systems Biology: Robustness, Modularity,and Redundancy

We humans are in essence complex biological machines,shaped over millennia by evolutionary forces and deﬁnedby our genome. All of the information necessary for lifeis encoded in our DNA. However, its utilization isdependent on the cellular context in which it resides,allowing the development, organization, and sustain-ment of the diverse set of cells that comprise us. Theability of the genome to generate and coordinate this

Division of Gastroenterology and Hepatology, Center for BasicResearch 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 StreetSW, Rochester, MN 55905.Genetics and Genomics of Complex Diseases in Hepatology; GuestEditor, Konstantinos N. Lazaridis, M.D.Semin Liver Dis 2007;27:3–12. Copyright

2007 by ThiemeMedical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,USA. Tel: +1(212) 584-4662.DOI 10.1055/s-2006-960167. ISSN 0272-8087.

tremendous level of diversity has evolved over the billionsof years that DNA-based life has existed.

2,3

Robustness isthe driving force behind this process and is a fundamentalfeatureofcomplexbiologicalsystems.

Simplyput,robustproperties provide phenotypic stability in the presence of unpredictable environmental orgenetic challenges.Com-plex systems become robust through modularity andredundancy, both of which act to mitigate the potentialfor system-wide damage.

Modular structure is pervasivein 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 andpathways 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 orpathways generating redundancy,

a compensatory proc-ess to achieve the desired phenotype when failure inanother gene or module occurs (Fig. 1). Thus, redun-dancy can and often does generate disconnect betweengenotype and phenotype, a process that is dependent onhigher order pathway and network interactions and thecontext in which the genome is utilized.

8,9

These funda-mental features of complex biological systems signiﬁ-cantly affect the genetic mechanisms underlying theetiology of complex human disease and pose limits onour current ability to study them.

Disease Genetics

Genetic predisposition is thought to play a role in mosthuman diseases.

Currently, three classiﬁcations basedon genetic involvement with disease are recognized:chromosomal, Mendelian, and complex.

Chromosomaldisorders are characterized by gross abnormalities inchromosome number or structure and often result inpreterm death related to developmental abnormalities.

Figure 1

Interconnected biological pathways generate redundancy. The interrelation of numerous pathways generates a redundantnetwork, buffering the effect of input variability and genetic polymorphism on phenotype. Shown is a simpliﬁed hypothetical signalingnetwork through which phenotypic effects are stimulated by a primary input that is detected by members of two distinct modularpathways (delineated by boxes). In this example, these pathways communicate through a

primary node

(dark gray square) that acts tomediate a large portion of the signal in the network and provides a feedback loop to diminish the effect of input variation on thephenotype(illustratedbydottedlines).However,someofthesignalfromeachpathway,aswellasa

secondary input

(darkgraycircle),isable to bypass this node and directly stimulate an effect on phenotype. Genetic polymorphism in individual components of the network(i.e.,genes)isunlikelytohaveagreateffectonphenotypebecauseofthemanymeansthroughwhichtheinputstimuluscanbepassed.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.

SEMINARS IN LIVER DISEASE/VOLUME 27, NUMBER 1 2007

Mendelian diseases run in families and display classicpatterns of inheritance, such as autosomal dominant,autosomal recessive, or X-linked. In general, thesedisorders are rare, arise early in life, and can be attributedto mutation in a single gene that, when present, directly causes the disease phenotype. Often these causativemutations are family speciﬁc. The vast majority of human diseases are genet-ically complex, wherein the direct correspondence be-tween causative genotype and disease phenotypecharacteristic of Mendelian disorders is not present.

Instead, complex diseases develop as the cumulativeresult of environmental exposures, exerting their effectover time, in genetically susceptible individuals. There-fore, the genotypic components of complex diseases arenot causative but rather mediate disease risk. Many suchsusceptibility genotypes are expected for each complexdisorder, some of which are common to similar diseases(e.g., autoimmune disorders) and some of which may bedisease specific. Regardless, the individual contributing variants are likely to have only a slight contribution tothe overall risk of each specific disease in the affectedpopulation (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 complexdisorders to a series of disease traits or phenotypes forconsideration in genomic studies. These traits can bequalitative, such as the presence of a comorbid disease, anassociated diagnostic marker, or a previously determinedrisk factor. In addition, these traits could be quantitativemeasures such as age of disease onset, results of serumliver tests, or gene expression profiles. Comprehensivecharacterization, assessment, and utilization of thesetraits will be essential in the dissection of the geneticand environmental contributors to complex disease.Disease concordance in monozygotic (MZ) twinsis presently the best means for establishing the strengthof the inherited genetic determinates of complex dis-ease.

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 differencein disease concordance between MZ and dizygotic (DZ)twin pairs may provide additional insight into themechanisms at play in complex disease development.For example, large differences in disease concordancebetween MZ and DZ twin pairs could signify theinvolvement of numerous risk-modifying gene variantsand, conversely, slight differences in concordance mightimply a stronger shared-environment effect. However, itshould be noted that de novo genetic and/or epigeneticeffects prior to or after MZ twinning could have an effecton MZ disease concordance and MZ/DZ concordanceratios, obscuring the reality of the inherited geneticcontribution to disease.

Familial aggregation alsoprovides a way to estimate the genetic impact oncomplex diseases,

as family members share moregenetic material between themselves than with thegeneral population. Relative risk ratios (

) are oftenused to illustrate the risk of disease development in thefamilies of affected individuals. The

is calculated by dividing the prevalence of a complex disease amongfamily members (often speciﬁcally siblings,

) by theprevalence of the disease in the population at large.

Ingeneral, higher

values suggest a greater role of thegenetic component in disease.

GENOMICS

From the earliest stages of life the human genome isselectively activated in response to both internal and

Figure 2

Comparison between Mendelian and complex diseases. In general, Mendelian diseases have lower frequency in thepopulation, display higher prevalence, and are caused by a single or a few genes, each of which has a high effect on the diseasephenotype. In contrast, complex diseases are usually more common, have reduced prevalence, and are mediated by several tonumerous genes, each of which has a small contribution to the phenotype.

APPLYING GENOMICS TO THE STUDY OF COMPLEX DISEASE

JURAN, LAZARIDIS