SCOPE
The goals of genetic epidemiology contrast with those of “traditional” epidemiology and population genetics. “Traditional” epidemiology studies the relationship between the environment and the incidence of a given disease, although it recognizes the significance of the host and his or her genetic makeup. Population genetics, on the other hand, seeks to predict the influences of population structure and selection and mutation on bodily phenotypes and diseases. Finally, genetic epidemiology studies the way environmental risk factors interact with the genetic makeup of a given population.
Further the scope of genetic epidemiology has expanded to include common diseases for which many genes each make a contribution (polygenic, multifactorial or multigenic disorders). Human Genome Project has led to study the association between diseases and genotypes. Advancement in the technology made it feasible to conduct large-scale genome-wide association studies. Genetic epidemiology is relatively new discipline that seeks to unravel the role of genetic factors and their interactions with environmental factors in the etiology of diseases, using population/family study approaches.
METHODS OF GENETIC EPIDEMIOLOGY
Genetic epidemiology uses two types of research strategies: descriptive and analytic. The descriptive strategy, at the population as well as at the family level, is based on the study of time, location, and the individual.
(a) Family Recurrence Studies
A fundamental aspect of genetic epidemiology is the study of aggregation (or recurrence) of certain diseases in given families. Is this familial aggregation associated with common environmental exposure, hereditary susceptibility, or cultural inheritance of risk factors? If there is genetic susceptibility, how is it inherited? The existence of familial aggregation can be determined by observing the prevalence of a given disease in family members of the index case (the index case is the affected individual who introduces the family into the study) and of controls (individuals who are not affected). This method is efficient and inexpensive, but one of its limitations is that information about characteristics of family members and controls may give rise to biased.
( b) Twin studies
Twin studies have typically been used to determine whether genetic factors play a role in the etiology of certain diseases. Such studies consist of comparing the difference in concordance between identical or monozygotic twins (MZ) and fraternal or dizygotic twins (DZ). MZ twins share 100% of their genetic material, whereas DZ twins share, on average, 50% of their genes. If sets of twins are being studied, and the MZ twins are found to be concordant (both have the same disease, for example) with greater frequency than the DZ twins, it is possible to conclude that genetic factors are at least partially involved in the etiology of that disease. It is important to note, however, that genetic differences may exist between MZ twins. They may differ, for example, in the series of T-cell antibodies and receptors, in the number of mitochondrial deoxyribonucleic acid (DNA) molecules, in somatic mutations in general, and in the inactivation pattern of the X chromosome in female twins. It is also well known that MZ twins may differ from DZ twins as a result of environmental factors. One of two calculations is normally made in twin studies, based on the method used to select the twins: (1) pair concordance rate, which describes the proportion of twin pairs where both siblings are affected; and (2) index case concordance rate, which is the proportion of affected individuals among the co-twins of those selected as index cases. Although the pair concordance rate is the simplest method of determining whether genes affect a specific phenotype, it does not measure the magnitude of such an effect. For that purpose, use of the index case concordance rate is preferable. Twin studies are limited by several factors; in particular those associated with the way participants are selected for the studies. For example, it has been observed that studies that depend exclusively on volunteers have a greater proportion of MZ twins, female pairs, and participants who are concordant for the phenotype under study. Such differences may influence the concordance rate that is calculated, which is why several countries— Sweden is a prime example—have launched population-based twin registries. Another limitation, especially in behavior studies, is that MZ twins tend to share environmental factors more frequently than DZ twins.
Allelic Association Studies
- 1) The allele in question is actually the cause of the phenotype.
- 2) The allele does not cause the phenotype but is in linkage disequilibrium with the causal allele. Linkage disequilibrium takes place when the causal allele of the phenotype is physically close (or linked) to the allele being studied.
The steps, a genetic epidemiologic research follows, are:
- 1) Establishing that there is a genetic component of the disorder.
- 2) Establishing the relative size of that genetic effect in relation to other sources of variation in disease risk (environmental effects such as intrauterine environment, physical and chemical effects as well as behavioral and social aspects).
- 3) Identifying the gene(s) responsible for the genetic component.
All of these can be achieved either in family studies (segregation, linkage, association) or in population studies (association).
General methods employed in genetic epidemiology are:
- Genetic risk studies: What is the contribution of genetics as opposed to environment to the trait?
- Segregation analyses: What does the genetic component look like (oligogenic ‘few genes each with a moderate effect’, polygenic ‘many genes each with a small effect’, etc.)? What is the model of transmission of the genetic trait? Segregation analysis requires multi generation family trees preferably with more than one affected member.
- Linkage studies: What is the location of the disease gene(s)? Linkage studies screen the whole genome and use parametric or nonparametric methods such as allele sharing methods (affected sibling-pairs method) with no assumptions on the mode of inheritance, penetrance or disease allele frequency (the parameters). The underlying principle of linkage studies is the co segregation of two genes (one of which is the disease locus).
- Association studies: What is the allele associated with the disease susceptibility? The principle is the coexistence of the same marker on the same chromosome in affected individuals (due to linkage disequilibrium). Association studies focus on population frequencies, whereas linkage studies focus on concordant inheritance. Association studies have several practical advantages over linkage studies.