Principles of Genetics in the Context of Complex Disease

September 2006
Adapted from: A Framework for Genetics and Complex Disease, with permission of
the Foundation for Genetic Education and Counseling
Introduction
The history of human genetics, and especially genetic medicine, is largely a history built
on the analysis of single-gene characters. That history has influenced thinking in the
health-care and genetics communities about genetic and molecular mechanisms, about
disease, and about education and counseling. Now, however, the increasing ability to
identify genetic variations associated with common, complex diseases challenges the
community to build on that history and to refine and extend traditional insights in ways
that continue to improve outcomes for patients and families and that help to demonstrate
the benefits of genetic perspectives for all of health care.
The principles that follow, which always must be a work in progress, are intended to
guide educational efforts that address the expansion of genetics into the realm of common
complex diseases.
1. Disease is a byproduct of the genetic variation necessary for survival of our
species. As is the case in all species, some variations are detrimental to some
individuals in some environments. In human beings, such disadaptive variations
come to our attention as disease. Human fecundity might be as low as 25 percent,
which means that most human disease occurs in utero. Much disadaptive
variation, therefore, never comes to our attention, because it does not survive the
rigors of intrauterine selection.

2. The potential for variation (mutation) in any part of the human genome accounts
for most human biological variation and for the great variety in expression of
disease.

3. Although disease is a function of evolutionary processes, evolution is a

phenomenon of species, not individuals. Its mark of success is a reproducing
population whose individuals matter only in fulfilling the evolutionary
imperative.
4. Complex diseases are non-mendelian; they may show familial clustering, but no
clear segregation. Segregation of the phenotypes is the principal difference
between single-gene disorders and complex diseases: although the genes of
complex diseases segregate, their phenotypes do not.
5. The designation "complex disease" is more informative than the traditional
designation "multifactorial," because the latter term focuses on causative agents -

genes and environment - but not on mechanisms. The term "complex" requires
that one think not only about causative agents but also about physiological
mechanisms, including homeostatic processes, development, and evolution.
6. Complex diseases generally are more frequent than single-gene disorders. As the
frequency of sickle cell disease (about 1 in 400 African-Americans)
demonstrates, however, that criterion doesn't always define a complex disease.
Elevated frequency of single-gene disorders generally resulted from genetic drift
or selective advantage.
7. Both single-gene disorders and complex diseases are characterized by multiple
genetic, developmental, and environmental factors. In single-gene disorders,
however, one gene has a pronounced effect in producing the phenotype in
question.
8. Complex diseases such as cancer, heart disease, diabetes, and mental illness are
the major contributors to morbidity and mortality in developed and developing
countries alike. Single-gene disorders are individually rare (generally), and even
in the aggregate constitute a much smaller burden of disease and death than do
complex diseases.
9. If elevated frequency generally signals the presence of a complex disease, do
infections fall into this category? Although most people, including most health
professionals, might not immediately recognize a genetic basis for infection,
there is considerable evidence that genotype can affect susceptibility and
resistance to infection. Given that infections are a consequence of a contest
between two genotypes, with opportunities for variation in both, they resemble
all other diseases in potential for susceptibility and resistance.
10. Because of the pervasive effects of one gene, single-gene disorders may be
expressed regardless of the environment, whether cellular or external. Others
require specific stimuli, for example, phenylalanine in PKU, or many agents for
the hemolytic anemia of G6PD deficiency. In complex diseases, in contrast, the
expected expression is influenced by the products of multiple genes interacting
with environmental factors throughout development, maturation, and aging.
11. Complex diseases differ from single-gene disorders quantitatively in that multiple
gene products combine to produce a phenotype in the former. In the latter, the
products of one locus override the effects of products of other loci. Modifying
genes and genetic heterogeneity make single-gene disorders complex in their
own right, but not as multifarious as diseases that involve multiple genes and
multiple environmental variables.
12. Although single-gene and complex diseases differ quantitatively along a
continuum, they do not differ qualitatively; the relationship between genes,
proteins, and biological processes is the same in both types of disease.

13. In single-gene disorders, it often is easier to discern the relationship between

gene and phenotype, and we know the details of that relationship for many such
disorders. The relationship between genes, gene products, and phenotype is less
easily discerned in complex disorders, and we know only a few of the details for
a few such diseases
14. Reduced penetrance is the rule for complex disease, that is, the disease is not
always expressed even in the presence of the associated gene(s). The notion of
penetrance itself, however, will be less useful as we learn more about the genes,
gene products, and homeostatic mechanisms that underlie any given disease.
15. Variations associated with common, complex diseases occur in polymorphic
genes, which are likely to be older, in evolutionary terms, than are those
associated with the more rare, single-gene disorders. Research in molecular
biology demonstrates the evolutionary conservation of important genes, for
example, those associated with development. An understanding of evolutionary
conservation helps us to grasp the constraints on human development.
16. Single-gene disorders generally disrupt homeostasis in significant ways early in
development and are, therefore, often under heavy selective pressure. Complex
diseases also disrupt homeostasis in significant ways, but the effects are more
gradual, often culminating in onset later in life, sometimes after the affected
individual has reproduced. Complex diseases, therefore, generally are under less
heavy selective pressure, though the origins of a complex disease in any given
individual may have a very long history, dating even to intrauterine life.
17. The most prominent difference between single-gene and complex disorders is the
degree to which a single gene product disrupts homeostasis. If a gene product is
so deficient or dysfunctional that it does severe damage to the system in which it
functions, that disease is generally rare. In addition, the disease will nearly
always have early onset and will resist efforts to provide any specific treatment or
even management. On the other hand, consider a gene product that carries out its
functions adequately under some or even most circumstances, but fails when
other gene products with which it is integrated fail to function. The resulting
disease will be more frequent, likely will have later onset, and likely will be more
amenable to treatment. The difference is in the extent of homeostatic damage. A
population biologist might say there is a difference in selection pressure. Further,
a population biologist might say that the relationship of increasing frequency
with later onset is evidence of a decline in the weight of genetic contributions to
disease with age.
18. Common disorders generally are more amenable to treatment than are singlegene disorders. In the latter, the damage often occurs early in development and
often is resistant because of the severity and pervasiveness of the effects.
Although the impact of common diseases often is quite severe, those diseases
generally develop gradually, throughout the life span, often presenting in middle

age. The practitioner often can improve symptoms by modifying the contributing
environmental factors, for example, through diet, exercise, medication, or
counseling. Some common diseases also are amenable to early intervention, such
as the removal of precancerous lesions.
19. One often hears or reads the phrase, gene-environment interaction. Given that
genes exert their effects only through the specificity of the products they
determine, it is more appropriate to refer to the interactions between gene
products - proteins - and experiences of the environment. Proteins mediate
biochemical and molecular mechanisms at each level of biological organization,
from the molecular to the organismal.
20. It follows, then, that gene products are at the center of pathogenesis; proteins are
where the clinical model and the molecular model of disease meet. This
prominence is now evident in the use of new words. For example, the protein
repertoire is known as the proteome, a word that expresses its relationship to the
genome, while the business of sorting out the relation of proteins to their
functions is called proteomics.
21. In the context of disease, we are likely to associate "the environment" only with
matters external to the individual, for example, mutagens, carcinogens,
teratogens, pathogens, and other substances commonly experienced. A
consideration of common, complex disorders, however, requires an expanded
definition of the "the environment," beginning with the intracellular environment
and progressing to that created by the interaction of the individual with the
outside world. The environment for a given gene product, for example, may
include its interactions with those of other genes.
Consideration of the environment also requires recognition of the unique
developmental history and experiences of each individual, which result in each
person's coming to a given disease through a unique series of events. Diagnosis
therefore should include information from three time scales: that of the genes or
phylogeny, that of development or ontogeny, and that of the moment. The
expression of the disease will reflect elements of all three.
22. The explanation of causation generally is more difficult with common, complex
disorders than with single-gene disorders. Usually the names, nature, or number
of genes involved, and their products, will be unknown, as will the ways in which
those gene products interact, or the unique ways in which the experiences of the
environment have precipitated disease in any given individual.
Given that uncertainty, determinations of risk and susceptibility are problematic.
The risk for disease imparted by the same gene product can differ from family to
family, and even among the members of the same family, because heterogeneity
of genes, development, and experiences may be present within the family. For
example, a disease may involve five genes, any three of which can result in

disease. Each member of a given family may inherit different sets of these genes
from different parents. In addition, unknown environmental factors may
precipitate disease in some members of a family while other family members
who have the same genes remain unaffected.
23. Increasingly, genetic counselors and primary-care providers will be challenged to
explain the uncertainty produced by genetic variation and by our incomplete
understanding of its manifestations and implications. Counseling for living with
uncertainty, commonly required in health care, is likely to need new levels of
refinement.
24. In those cases where gene discovery makes possible susceptibility testing for
complex disease, providers must help patients make an informed decision about
genetic testing. That will require clear discussions about complex causation,
about the meaning of susceptibility, and about the limited predictive value of
positive or negative results.
25. Improved understanding of genetic and environmental contributions to complex
disease should shift the focus of health care from the name of the disease itself to
genetic individuality and to the individuality of the experiences, habits, and
conditions of the environment of the particular patient. This approach to health
care should make it more likely that the provider will look for the biological and
environmental circumstances that led a given person to express a given disease at
a given moment in his or her developmental history.
26. A focus on the genetic, developmental, and environmental components of
disease, and their unique combination in a given individual, inevitably will
require that health care emphasize prevention more than it does at present.
Indeed, once having established a genetic susceptibility to a complex disease,
providers will be left with no alternative except prevention to help the patient to
avoid those environmental factors that can provoke disease or to adopt regimes of
self examination that can detect early indications of illness.
27. As we come to understand the environmental contributions to complex disease,
we can, through education and political action, begin to eliminate them or at least
dilute their impact. In doing so, we would be creating an environment where the
remaining major contributions to disease are those that result from variants in the
human genome. In fact, that is the goal of disease prevention in which nongenetic variation is reduced, and it is the trajectory of health care informed by
genetic perspectives.

The table below summarizes the similarities and differences between single-gene and
complex disorders.
Summary of Similarities and Differences between Single-gene and Complex Disorders

CHARACTERISTICS

SINGLE GENE

COMPLEX

Genes

Segregate

Segregate

Disorder

Segregates

Clusters

Primarily one

Multiple

Often overridden by
effect(s) of gene mutation
Often younger

Important
Often older

Selection

Often significant

Generally not significant

Risks for relatives of

probands
Cumulative healthcare
burden
Prevalence

More predictable,
often larger
Lower

Less predictable,
often smaller
Higher

Relatively rare

Common

Variability in symptom
expression
Treatment

Generally less variable

Generally more variable

Often ineffective

More likely effective

Number of gene products

Role of environment
Age at onset

By Barton Childs, M.D.

and Joseph D. McInerney, M.A., M.S.