Principles of Genetics in the Context of Common Disease

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.

Principles of Genetics in the Context of Common Disease

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• Common disorders generally are more amenable to treatment than are single gene 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

Authors: Barton Childs, M.D. and Joseph D. McInerney, M.A., M.S. (2006)

Adapted from “A Framework for Genetics and Complex Disease,” with permission of the Foundation for Genetic Education and Counseling.