Scand J Soc Med, Vol. 20, No.4
Genetic epidemiology - possibilities and problems Per Magnus From the Department of Epidemiology, National Institute of Public Health, 0462 Oslo, Norway
Genetic epidemiology - possibilities and problems. Magnus, P. (Department of Epidemiology, National Institute of Public Health, 0462 Oslo, Norway). Scand J Soc Med 1992, 4 (193-195).
Genetic epidemiology is a new field, fuelled by the scientific revolution in molecular genetics. The International Society for Genetic Epidemiology was founded in October 1991, in conjunction with the International Congress of Human Genetics. Why should classical epidemiologists, environmentally oriented as they are, concern themselves with genes? There are three main reasons. The first is that classical epidemiology in developed societies may be reaching the limits of what can be achieved in etiology by continuing to only measure environmental exposure. There is little reason to expect quantum leaps in etiological understanding of, for instance, the relationship between diet and cancer, by continued case-control or cohort studies, focussing only on the environmental side. For many chronic diseases, such as schizophrenia, rheumatoid arthritis, multiple sclerosis, hypertension or diabetes, the etiological insight is minimal, despite numerous epidemiological studies. The second reason is that it will be easier to assess the possibilities for prevention of disease by alterations of environmental exposure, when the interaction between genetic liability and environment is understood. The third reason is that epidemiologists must help the molecular biologists in determining whether candidate genes have etiological importance, so that laboratory work can be continued in the right direction. But knowledge about genetic etiology in common diseases opens unwanted scenarios to many workers in public health. What if modern societies, concerned with the high expenditures in health and social welfare, decide to discriminate on a genetic basis? Predictive medicine can be an unpleasant con-
cept if private or governmental employers, insurance companies or health services choose to give their support only if a person has the right genes. Thus, apart from the scientific challenges, there are problems with genetic epidemiology. New knowledge about effects of genes in causing common chronic disorders forces us to have opinions about how this information should be taken into use. The scientific community has discussed and must continue to discuss the ethical and social implications. The scientific community must also continue to emphasize that the concept of the "right gene" has no absolute meaning, since a gene which is beneficial in one setting may cause disease in another. Genetic variability in the population is a necessary buffer for our future survival in a world with rapid environmental changes. What, then, is genetic epidemiology? First, let us look at how genetics and epidemiology have come closer to each other. For understanding the relation between genes and disease in monogenic disorders and chromosomal abberations, medical geneticists have managed without the aid of epidemiology. When molecular genetics arrived on the scene, it meant that single disease genes could be assigned to specific loci on the chromosomes using linkage analysis (1). It is now merely a matter of time and effort, as evidenced by the human genome projects in Europe, the United States and Japan, before the whole genome is sequenced and before most disease genes causing monogenic disorders ~re characterized biochemically. In addition, medical geneticists have for a long time used segregation analysis in pedigree studies to detect major gene effects for diseases that have a substantial genetic component (1). A more esoteric effort in human genetics has been the field of quantitative genetics, which has meant the study of genetic and environmental contributions to the population variability in traits and diseases at the phenotypic level, using twin studies, adoption studies or Scand J Soc Mcd 20
13 Social Medicine
Downloaded from sjp.sagepub.com at Karolinska Institutets Universitetsbibliotek on May 23, 2015
194
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other special designs (2). Finally, population geneticists have analysed the distribution of single genes in populations in their studies of mutation, selection and chance as processes of evolution (3). Based on developments in population genetics, Morton (4) defined genetic epidemiology as: "A science that deals with etiology, distribution, and control of disease in groups of relatives and with inherited causes of disease in populations". He adds that: "Inherited, as here used in the broad sense, includes both biological and cultural inheritance. The set of relatives may be as close as twins or as extended as an ethnic group". However, scientists working in these traditions have seldom measured environmental exposures on an individual level. Conversely, for epidemiologists, genes have been looked upon as important background factors, but since we can do nothing about them, they are noise in the system. One has carefully avoided studying genetic influences by drawing random samples of unrelated subjects in epidemiological projects. At best, one has included questions on whether closely related relatives of the responder have suffered from the disease of interest. It is interesting to note that one of the first modern textbooks in epidemiology, published in 1970 (5), included a chapter on genetics and epidemiology, but that later textbooks have only marginally mentioned genetic factors. In recent years, however, the term molecular epidemiology has been used by many epidemiologists, but then mainly to indicate pathogenic mechanisms, such as genetic damage caused by environmental factors. Biological markers as indicators of longterm environmental exposure or of a certain toxicological influence arc increasingly used (6). The quantification of selenium in toenails is an example of an indicator of longterrn dietary intake, while the study of DNAadducts or the examination of changes in oncogenes represent ways of pinpointing the damage done by environmental agents. Genetic epidemiology is something more than the fields mentioned above. It is really only today, when candidate genes for several chronic diseases appear on the stage, that the field can open up. Genetic epidemiology implies the simultaneous study of single genes and environmental exposures in such a way that interactions can be elucidated (7). These interactions can be studied with ordinary epidemiological designs, such as case-control studies. One is looking for genes that significantly modulate the risk that a certain subject with a certain environmental expo-
sure will suffer from a disease. Candidate genes may be alleles at loci where mutations have been shown to cause monogenic diseases. Examples may be alleles at the loci regulating the activity of the low density lipoprotein receptor for better understanding of host susceptibility to coronary heart disease (8), or alleles at the amyloid protein locus in the study of Alzheimer's disease (9). The genes may be suggested on other grounds, for instance that they are known to code for enzyme activity or for structures in the build-up of cells and organs, and that it is biologically plausible that these structures or enzymes influence the disease in question. Molecular geneticists can only suggest genes to study. It is not possible in the laboratory to determine whether a suggested gene plays a major role in the etiology of a common disease. Population studies must be performed, employing the epidemiological concepts and tools that have been developed in recent decades. When a gene is found to be of significant importance as a result of epidemiology, the molecular biologists can devote their efforts to this gene and can perform "reverse genetics" in order to find out what the gene product is and how metabolism or structure is altered, opening up prospects for therapeutic intervention. It is in this perspective that genetic epidemiology has its potential. As demonstrated, molecular biology and epidemiology depend on each other. Interestingly, the pace in the development of understanding etiology will be set by the epidemiologists, not by the geneticists. This will be more obvious in the coming years, when we have become used to the concept of candidate genes, and have sorted out the best study designs. Perhaps the whole concept of genetic epidemiology is unnecessary. It is probably better to say that epidemiology is the study of "the importance and interaction of genetic and environmental factors in the etiology of disease.
REFERENCES 1. Vogel F, Motulsky AG. Human genetics - problems and approaches. Berlin: Springer-Verlag, 1982. 2. Falconer DS. Introduction to quantitative genetics. 2nd ed. London: Longman Group, 1981. 3. Dobzhansky T, Ayala FJ, Stebbins GL, Valentine JW. Evolution. San Franscisco: WH Freeman, 1977. 4. Morton NE. Outline of genetic epidemiology. Basel: Karger, 1982.
Scand J Soc AIi'd 20
Downloaded from sjp.sagepub.com at Karolinska Institutets Universitetsbibliotek on May 23, 2015
Genetic epidemiology
195
J
5. Maclvlahon D Pugh TF Eni d . methods. Do s~oO" Lilli . DPI crniology - principles and . c, rown and Co 1970 6 HI'. . u "a DS, Wilcosky TC G iffi I ., . n It I JD. Biological markers in epidemiology Press , 1990. "' . ew York : O xford University
9. Hardy J, Allsop D Am loid .. event in the aet iol~ gy Al z~ cpo sl .lOn.as the cen tral Pharmacol Sci 1991; 12: 383-8 . elmer s disease . Trend s
7.
Address for offp rints: Per Magnus D e ~t of Epidemiology Nat ional Institut e of Publi c H I h N-O.f62 Oslo ea t Nor way.
N
Kho~ry MJ, Adams jr MJ, H and . ologic approach to ecogenetics AersJ \H~D. An epidemi. m urn Genet 1988; 42: 89-95.
8. Gold ste in JL , Drown MS T regulati on of cellula r chol~st he ILDL r ee ~ ptor and the 1985; Suppl 3: 131-7. ero metabohsm. J Cell Sci
ON LOAN FROM BLDSC BOSTON SPA. FOR USE IN ST. PANCRAS SCIENCE 2 SOUTH READING ROOM ONLY RETURN DATE
~\\
AEC-I
Scand J Soc M~d 20
13'
Downloaded from sjp.sagepub.com at Karolinska Institutets Universitetsbibliotek on May 23, 2015
Genetic epidemiology - possibilities and problems Per Magnus From the Department of Epidemiology, National Institute of Public Health, 0462 Oslo, Norway
Genetic epidemiology - possibilities and problems. Magnus, P. (Department of Epidemiology, National Institute of Public Health, 0462 Oslo, Norway). Scand J Soc Med 1992, 4 (193-195).
Genetic epidemiology is a new field, fuelled by the scientific revolution in molecular genetics. The International Society for Genetic Epidemiology was founded in October 1991, in conjunction with the International Congress of Human Genetics. Why should classical epidemiologists, environmentally oriented as they are, concern themselves with genes? There are three main reasons. The first is that classical epidemiology in developed societies may be reaching the limits of what can be achieved in etiology by continuing to only measure environmental exposure. There is little reason to expect quantum leaps in etiological understanding of, for instance, the relationship between diet and cancer, by continued case-control or cohort studies, focussing only on the environmental side. For many chronic diseases, such as schizophrenia, rheumatoid arthritis, multiple sclerosis, hypertension or diabetes, the etiological insight is minimal, despite numerous epidemiological studies. The second reason is that it will be easier to assess the possibilities for prevention of disease by alterations of environmental exposure, when the interaction between genetic liability and environment is understood. The third reason is that epidemiologists must help the molecular biologists in determining whether candidate genes have etiological importance, so that laboratory work can be continued in the right direction. But knowledge about genetic etiology in common diseases opens unwanted scenarios to many workers in public health. What if modern societies, concerned with the high expenditures in health and social welfare, decide to discriminate on a genetic basis? Predictive medicine can be an unpleasant con-
cept if private or governmental employers, insurance companies or health services choose to give their support only if a person has the right genes. Thus, apart from the scientific challenges, there are problems with genetic epidemiology. New knowledge about effects of genes in causing common chronic disorders forces us to have opinions about how this information should be taken into use. The scientific community has discussed and must continue to discuss the ethical and social implications. The scientific community must also continue to emphasize that the concept of the "right gene" has no absolute meaning, since a gene which is beneficial in one setting may cause disease in another. Genetic variability in the population is a necessary buffer for our future survival in a world with rapid environmental changes. What, then, is genetic epidemiology? First, let us look at how genetics and epidemiology have come closer to each other. For understanding the relation between genes and disease in monogenic disorders and chromosomal abberations, medical geneticists have managed without the aid of epidemiology. When molecular genetics arrived on the scene, it meant that single disease genes could be assigned to specific loci on the chromosomes using linkage analysis (1). It is now merely a matter of time and effort, as evidenced by the human genome projects in Europe, the United States and Japan, before the whole genome is sequenced and before most disease genes causing monogenic disorders ~re characterized biochemically. In addition, medical geneticists have for a long time used segregation analysis in pedigree studies to detect major gene effects for diseases that have a substantial genetic component (1). A more esoteric effort in human genetics has been the field of quantitative genetics, which has meant the study of genetic and environmental contributions to the population variability in traits and diseases at the phenotypic level, using twin studies, adoption studies or Scand J Soc Mcd 20
13 Social Medicine
Downloaded from sjp.sagepub.com at Karolinska Institutets Universitetsbibliotek on May 23, 2015
194
Per Magnus
other special designs (2). Finally, population geneticists have analysed the distribution of single genes in populations in their studies of mutation, selection and chance as processes of evolution (3). Based on developments in population genetics, Morton (4) defined genetic epidemiology as: "A science that deals with etiology, distribution, and control of disease in groups of relatives and with inherited causes of disease in populations". He adds that: "Inherited, as here used in the broad sense, includes both biological and cultural inheritance. The set of relatives may be as close as twins or as extended as an ethnic group". However, scientists working in these traditions have seldom measured environmental exposures on an individual level. Conversely, for epidemiologists, genes have been looked upon as important background factors, but since we can do nothing about them, they are noise in the system. One has carefully avoided studying genetic influences by drawing random samples of unrelated subjects in epidemiological projects. At best, one has included questions on whether closely related relatives of the responder have suffered from the disease of interest. It is interesting to note that one of the first modern textbooks in epidemiology, published in 1970 (5), included a chapter on genetics and epidemiology, but that later textbooks have only marginally mentioned genetic factors. In recent years, however, the term molecular epidemiology has been used by many epidemiologists, but then mainly to indicate pathogenic mechanisms, such as genetic damage caused by environmental factors. Biological markers as indicators of longterm environmental exposure or of a certain toxicological influence arc increasingly used (6). The quantification of selenium in toenails is an example of an indicator of longterrn dietary intake, while the study of DNAadducts or the examination of changes in oncogenes represent ways of pinpointing the damage done by environmental agents. Genetic epidemiology is something more than the fields mentioned above. It is really only today, when candidate genes for several chronic diseases appear on the stage, that the field can open up. Genetic epidemiology implies the simultaneous study of single genes and environmental exposures in such a way that interactions can be elucidated (7). These interactions can be studied with ordinary epidemiological designs, such as case-control studies. One is looking for genes that significantly modulate the risk that a certain subject with a certain environmental expo-
sure will suffer from a disease. Candidate genes may be alleles at loci where mutations have been shown to cause monogenic diseases. Examples may be alleles at the loci regulating the activity of the low density lipoprotein receptor for better understanding of host susceptibility to coronary heart disease (8), or alleles at the amyloid protein locus in the study of Alzheimer's disease (9). The genes may be suggested on other grounds, for instance that they are known to code for enzyme activity or for structures in the build-up of cells and organs, and that it is biologically plausible that these structures or enzymes influence the disease in question. Molecular geneticists can only suggest genes to study. It is not possible in the laboratory to determine whether a suggested gene plays a major role in the etiology of a common disease. Population studies must be performed, employing the epidemiological concepts and tools that have been developed in recent decades. When a gene is found to be of significant importance as a result of epidemiology, the molecular biologists can devote their efforts to this gene and can perform "reverse genetics" in order to find out what the gene product is and how metabolism or structure is altered, opening up prospects for therapeutic intervention. It is in this perspective that genetic epidemiology has its potential. As demonstrated, molecular biology and epidemiology depend on each other. Interestingly, the pace in the development of understanding etiology will be set by the epidemiologists, not by the geneticists. This will be more obvious in the coming years, when we have become used to the concept of candidate genes, and have sorted out the best study designs. Perhaps the whole concept of genetic epidemiology is unnecessary. It is probably better to say that epidemiology is the study of "the importance and interaction of genetic and environmental factors in the etiology of disease.
REFERENCES 1. Vogel F, Motulsky AG. Human genetics - problems and approaches. Berlin: Springer-Verlag, 1982. 2. Falconer DS. Introduction to quantitative genetics. 2nd ed. London: Longman Group, 1981. 3. Dobzhansky T, Ayala FJ, Stebbins GL, Valentine JW. Evolution. San Franscisco: WH Freeman, 1977. 4. Morton NE. Outline of genetic epidemiology. Basel: Karger, 1982.
Scand J Soc AIi'd 20
Downloaded from sjp.sagepub.com at Karolinska Institutets Universitetsbibliotek on May 23, 2015
Genetic epidemiology
195
J
5. Maclvlahon D Pugh TF Eni d . methods. Do s~oO" Lilli . DPI crniology - principles and . c, rown and Co 1970 6 HI'. . u "a DS, Wilcosky TC G iffi I ., . n It I JD. Biological markers in epidemiology Press , 1990. "' . ew York : O xford University
9. Hardy J, Allsop D Am loid .. event in the aet iol~ gy Al z~ cpo sl .lOn.as the cen tral Pharmacol Sci 1991; 12: 383-8 . elmer s disease . Trend s
7.
Address for offp rints: Per Magnus D e ~t of Epidemiology Nat ional Institut e of Publi c H I h N-O.f62 Oslo ea t Nor way.
N
Kho~ry MJ, Adams jr MJ, H and . ologic approach to ecogenetics AersJ \H~D. An epidemi. m urn Genet 1988; 42: 89-95.
8. Gold ste in JL , Drown MS T regulati on of cellula r chol~st he ILDL r ee ~ ptor and the 1985; Suppl 3: 131-7. ero metabohsm. J Cell Sci
ON LOAN FROM BLDSC BOSTON SPA. FOR USE IN ST. PANCRAS SCIENCE 2 SOUTH READING ROOM ONLY RETURN DATE
~\\
AEC-I
Scand J Soc M~d 20
13'
Downloaded from sjp.sagepub.com at Karolinska Institutets Universitetsbibliotek on May 23, 2015
