Identifying the Roles of Genetic and Environmental Factors in Disease Causation PDF

## Identifying the Roles of Genetic and Environmental Factors in Disease Causation ### Learning Objectives * To examine how epidemiologic study designs can clarify the roles of genetic and environmental factors in risk of disease and their possible interactions. * To show how genetic markers are u...

## Identifying the Roles of Genetic and Environmental Factors in Disease Causation ### Learning Objectives * To examine how epidemiologic study designs can clarify the roles of genetic and environmental factors in risk of disease and their possible interactions. * To show how genetic markers are used to map genes controlling risk of different diseases, including complex diseases.. * To test for interaction between genes and environmental risk factors. * To discuss how innovative epidemiologic and molecular biology methods can help to define the etiologic roles of environmental and genetic risk factors, and potentially permit development of individualized treatments of disease. ### Traditional Genetics Traditional medical genetics has focused primarily on single-gene traits that follow the transmission patterns outlined by Gregor Mendel, a 19th century Austrian monk. Mendelian diseases are typically rare in the population, and can be classified by their transmission as autosomal dominant, autosomal recessive, X-linked dominant, or X-linked recessive. Some Mendelian diseases, for example, cystic fibrosis (the most common autosomal recessive disease in populations of Northern European ancestry, with a birth prevalence of 1/2,500 livebirths among non-Hispanic whites in the United States) and sickle cell disease (the most common hemoglobinopathy among populations of West African ancestry with a birth prevalence of 1/360 live births) ### Complex Diseases Most human diseases, however, are controlled by a combination of genetic and environmental factors acting together. The spectrum of genetic control over diseases varies from strictly genetic to strictly environmental, and some diseases fall in the middle range where both genes and environmental factors influence risk. These include some congenital malformations and cancers, where there is strong and compelling evidence for familial aggregation of risk (the hallmark of genetic control), but also recognized environmental risk factors (e.g., in utero exposure to viruses, exposures to carcinogens for cancers, etc.). Unlike the traditional single gene diseases, a complex disease likely reflects effects of one or more genes (that may interact with each other) and the environment, and there is often some degree of etiologic heterogeneity where multiple genes can lead to disease. ### How Epidemiologic Study Designs Can Clarify the Roles of Genetic and Environmental Factors in Risk to Disease If genetic factors do influence risk of disease, relatives of cases (individuals with the disease) should be at a higher risk than relatives of controls (individuals without the disease). Reliable information can be garnered on first-degree relatives (parents, siblings, and children), and most individuals have some information on second-degree relatives (half-siblings, avuncular relatives, grandparents/ grandchildren, etc.). ### Twin Studies Studies of twins have been of great value in identifying the relative contributions of genetic and environmental factors to the causation of human disease. * **Monozygotic or MZ (identical) twins:** arise from the same fertilized ovum and share 100% of their genetic material. * **Dizygotic or DZ (fraternal) twins:** are genetically like other siblings and thus share on average 50% of their genetic material. If MZ twins are concordant for a disease, it could be either genetic or environmental, however if MZ twins are discordant for a disease, it is at least partly environmental in origin. In DZ twins both environmental and genetic factors are operating. If a disease is genetic, we would expect lower concordance in DZ twins than in MZ twins. ##### How to calculate rates of concordance and discordance in twins | | | | | |--------------------------|------------------------|-------|-------| | **Twin 1** | **Has Disease** | **Have Disease** | **Does Not Have Disease**| | **Twin 2** | **Has Disease** | a | b | | | **Does Not Have Disease** | c | d | **Concordance rate in twin pairs where at least one twin has the disease:** $$\frac{a}{a+b+c}$$ **Discordance rate in all twin pairs where at least one twin has the disease** $$\frac{b+c}{a+b+c}$$ ### Adoption Studies Adopted children are used to compare the relative contributions of genetic and environmental factors to the cause of disease. * **Offspring of normal biologic parents reared by schizophrenic adopting parents** * **Offspring of normal biologic parents reared by normal adopting parents** * **Offspring of schizophrenic biologic parents reared by normal adopting parents** ### Time Trends in Disease Incidence If we observe time trends in disease risk with incidence either increasing or decreasing over a relatively short period of time, and if we are convinced that the trend is real, the observation implicates environmental factors in the causation of the disease. ### How Genetic Markers Are Used to Map Genes Controlling Risk to Diseases, Including Complex Diseases Genetic markers are variants in DNA sequence that can be typed directly. Markers are transmitted from parent to offspring clearly following regular Mendelian patterns, and the chromosomal locations of genetic markers are generally known. ### Linkage Analysis in Family Studies It is valuable to examine the first-degree relatives for evidence of a greater-than-expected prevalence of disease. Excess risk in first-degree relatives suggests the existence of genetic factors. ### Association Studies Similar to the approach of testing for familial aggregation of disease we can also test for an association between an SNP and a disease (or a continuous phenotype). The feasibility of studying the entire genome to identify genetic associations, in the form of genome-wide association studies (GWAS), has changed the overall approach for studying associations between genetic markers (most often SNPs) and disease. ### Interaction Between Genetic and Environmental Risk Factors The question of genetic susceptibility to environmental factors and the possibility of interaction between them must also be addressed. An example of interaction is smoking and the factor V Leiden mutation. Smoking is a known risk factor for myocardial infarction (MI), and factor V Leiden is a common hereditary abnormality that affects blood clotting and increases the risk of venous thrombosis. ### Precision Medicine Sequencing technology is now driving the current era of genetic epidemiology. This new phase has been driven by two forces: (1) the advancements in massive parallel or "next-generation sequencing" technology that is becoming affordable even for samples sizes seen in epidemiologic studies and (2) the impending completion of combined GWAS analyses for many (if not most) complex diseases across large studies, which has identified numerous genes as significantly influencing risk. We have not reached our goal of fully understanding complex diseases (and we might be far from it) if causal pathways involve mechanistic gene-gene and gene-environment interactions. ### Prospects for the Future Despite the excitement accompanying sequencing the human genome and the results of genome-wide studies described earlier, for most complex diseases (in which both genetic and environmental factors have been implicated) the current data are still not sufficient to specifically delineate how genes contribute to risk. ### Conclusion This chapter has described some of the epidemiologic approaches used to assess the relative contributions of genetic and environmental factors in causing human disease. The link of epidemiology and genetics has become increasingly recognized, and a field called genetic epidemiology has emerged. Most epidemiologic studies are directed at identifying environmental factors in controlling the risk of disease, but when designing and conducting studies and interpreting their results, it is important to bear in mind that individuals in epidemiologic studies differ not only in environmental exposures but also in their genetic makeup and this too influences risk. When appropriate, epidemiologic studies of risk factors, including case-control and other study designs, should be expanded to include gathering family histories and obtaining biologic samples whenever possible. Incorporating genetic advances and genetic markers into epidemiologic studies is proving increasingly invaluable in identifying high-risk subgroups and tailoring therapies specific to the individual. They are likely to become increasingly important in improving disease prevention in the future.