Gene and Environment

Questions of "nature versus nurture" have been asked of most human traits: Is it our genes, inherited from our parents, that make us the way we are, or is it the environment in which we live? A phenotype is a trait that can be observed and described in a population. Although some phenotypes may be totally controlled by genetic or environmental factors, most are influenced by a complex combination of the two. Genes and environmental factors may work independently, or they may interact with one another to cause the phenotype.

Classes of Human Genetic Phenotypes

Human phenotypes are often classified as either simple (or Mendelian) or complex. A "simple" or Mendelian phenotype is one that demonstrates a recognizable inheritance pattern (such as autosomal dominant or recessive, or X-linked). A Mendelian phenotype is caused by a particular genetic variant, or allele , of a gene. The expression of Mendelian phenotypes may vary by age, but, in general, the effect of a single gene is sufficient to cause the phenotype.

In contrast, "complex" phenotypes do not adhere to simple Mendelian laws, and they are influenced by several factors (either genetic or environmental) acting independently or together. In complex phenotypes, alleles of particular genes increase the probability that the phenotype will develop, but do not determine with certainty whether a person will have the phenotype. They are neither necessary nor sufficient to cause the phenotype. Genes that act in this fashion are called susceptibility genes. The complex interaction of susceptibility genes with other genetic and environmental risk factors determines whether or not a person will develop a complex phenotype.

Gene-Environment Interaction in Phenylketonuria

Phenylketonuria (PKU) is a classic example of gene-environment interaction. PKU was originally described as an autosomal recessive metabolic disease, in which people with two defective copies of the phenylalanine hydroxylase gene are unable to convert phenylalanine into tyrosine. This inability leads to an accumulation of phenylalanine in the blood, causing problems with nerve and brain development that result in mental retardation.

The treatment of PKU by removing foods containing phenylalanine from the diet (and thus reducing the accumulation of phenylalanine) demonstrated that mutations in the phenylalanine hydroxylase gene cause mental retardation only in the presence of dietary phenylalanine. Since phenylalanine is very common in the diet, this gene-environment interaction was not detected at first. PKU serves as an illustration that phenotypes that are apparently Mendelian in nature may have complex interactions with other genes and with the environment. Removing the exposure to dietary phenylalanine prevents mental retardation, and phenylalanine does not cause mental retardation in the absence of mutations in the phenylalanine hydroxylase gene. Therefore, both factors are needed to cause mental retardation due to PKU.

The identification of the gene-environment interaction in PKU has led to the effective treatment of this genetic disorder. Individuals who carry mutations in the phenylalanine hydroxylase gene, if placed on a lowphenylalanine diet, generally do not develop the symptoms of PKU. To identify individuals at risk of PKU, newborns are screened for elevated phenylalanine levels in the blood. Those infants with positive screening tests are then evaluated further. Those with PKU (about 1 in 10,000 live births) are then placed on low-phenylalanine diets to prevent the development of mental retardation.

Methods for Identifying Gene-Environment Interactions

As the example of PKU demonstrates, studies that attempt to identify factors important in determining human phenotypes must simultaneously examine multiple genetic and environmental factors. It is generally not possible to experiment directly on humans to observe the effects of a gene or environmental factor on the expression of a phenotype. Human genetic studies are generally observational studies, where the researcher is limited to observing the combinations of exposures that naturally occur in the population. Genetic epidemiologists must apply statistical methods to these observational data to evaluate how genes and the environment affect the development of a phenotype .

The simultaneous analysis of genetic and environmental factors allows the identification of environmental factors that interact with each other. Researchers use statistical models to compare the joint effects of genetic and environmental factors in people with the phenotype and people without the phenotype. Such "case-control studies" are commonly used to examine the relationship between disease phenotypes and both genetic and nongenetic risk factors.

The strength of the association between a risk factor and the disease is described by the "relative risk," which is the probability of having the phenotype if exposed to the risk factor divided by the probability of having the phenotype if not exposed to the risk factor. A relative risk greater than 1 suggests that the risk factor increases the probability of developing the phenotype, whereas a relative risk less than 1 suggests the risk factor decreases the probability of the phenotype. An association between a risk factor and a phenotype exists if the relative risk is significantly different from 1.

An example of a risk factor and relative risk can be seen in Alzheimer's disease (AD). One gene that influences the risk of AD is the APOE gene. Three common alleles are known: ε-2, ε-3, and ε-4. Caucasian Americans with one or more copies of ε-4 are two and one-half times more likely to develop AD than are people with two ε-3 alleles. Interestingly, the ε-4 allele is not as strong of a risk factor for AD among African Americans or Hispanics, who nonetheless have higher risks of developing AD than Caucasians.

Patterns of Gene-Environment Interactions

There are many potential patterns of interaction that could exist between genetic and environmental factors for a phenotype. Several plausible statistical models of gene-environment interaction have been described. Phenotype expression can either be:

1. Increased only in the presence of both the susceptibility genotype and the environmental factor;
2. Increased by the environmental factor alone but not by the genotype alone;
3. Increased by the genotype alone but not by the environmental factor alone;
4. Increased by either, with joint effects being additive or multiplicative;
5. Reduced by the genotype and not affected by the environmental factor alone, but increased in the presence of both; or
6. Reduced by the genotype, increased by the environmental factor, and increased by the presence of both.

These models are simple and consider the effect of only one gene and one environmental factor. Interactions are likely to be much more complex, involving multiple genes, multiple environmental factors, genetic heterogeneity, and heterogeneity of exposure. However, finding statistical interaction between two factors is just the first step in unraveling a complex phenotype. Once statistical interactions are identified, other laboratory studies may be performed to establish what biological interactions, if any, exist.

The level of cholesterol in the bloodstream is an example of a trait that is caused by a complex set of genetic and environmental factors. In families with familial hypercholesterolemia (FHC), elevated cholesterol levels are inherited in a Mendelian, autosomal dominant pattern. However, only about 4 percent of all individuals in the top 5 percent of cholesterol levels in the population carry the gene responsible for FHC. Other genetic and environmental risk factors clearly influence cholesterol levels. For example, in people with and without FHC, consumption of cholesterol in the diet independently modifies cholesterol levels. Other factors such as exercise and medication use likely interact with dietary intake to determine blood levels of cholesterol. Other genetic factors may also be involved.

With the exception of a relatively small number of phenotypes that are completely genetically determined, almost all human phenotypes represent a combination of environmental and genetic factors. Understanding the ways in which genes and environment work together to impact human health is one of the great challenges in the study of complex phenotypes.

see also Alzheimer's disease; Cardiovascular Disease; Complex Traits; Diabetes; Inheritance Patterns; Metabolic Disease; Statistics.

William K. Scott

Bibliography

Khoury, Muin J., Terri H. Beaty, and Bernice H. Cohen. Fundamentals of Genetic Epidemiology. New York: Oxford University Press, 1993.

Thompson, Margaret W., Roderick R. McInnes, and Huntington F. Willard. Thompson and Thompson: Genetics in Medicine, 5th ed. Philadelphia: W. B. Saunders Company, 1991.

Vogel, Friedrich, and Arno G. Motulsky. Human Genetics: Problems and Approaches, 2nd ed. Berlin: Springer-Verlag, 1986.