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10 Genetic Markers in Social Science Research: Opportunities and Pitfalls George P. Vogler and Gerald E. McClearn S ocial science survey research provides rich databases that are infor- mative regarding factors that influence the health and well-being of target populations. These studies frequently are rich in behavioral assessments that can include measures as diverse as cognitive assessment and personality characteristics, social support patterns, health behaviors, and the availability and utilization of health care services. Such research frequently has major advantages, including large, carefully selected sam- ples that are nationally representative or that target particular populations, frequently with long-term longitudinal data to monitor secular changes in risk and protective factors over time or over developmental periods. Examples of such research include such well-known studies as the Health and Retirement Study (HRS, Juster and Suzman, 1995), the National Long Term Care Survey (NLTCS, Research Triangle Institute, 2002), and the National Health and Nutrition Examination Survey (NHANES, Centers for Disease Control and Prevention, 2006). Recently there have been efforts to incorporate collection of DNA and other biomarkers into these types of surveys through the collection of blood samples or cheek swabs. The incorporation of genetic markers into studies that have health as an emphasis has the potential to provide a more thorough understanding of the mechanisms of the complex fac- tors that influence health outcomes, when considered with the other domains that are frequently assessed, including behavioral, psychologi- cal, social, economic, and environmental indicators. Studies such as the MacArthur Study of Successful Aging that have incorporated DNA and 194
GEORGE P. VOGLER and GERALD E. MCCLEARN 195 biological markers (Crimmins and Seeman, 2001) have demonstrated strong relationships between biological indicators and traditional demo- graphic variables and health outcomes. In the following discussion, issues are considered regarding the incorporation of DNA collection into studies that were designed to address social science questions. INCORPORATION OF DNA COLLECTION INTO SOCIAL SCIENCE SURVEYS Incorporation of DNA collection into social science surveys has the potential to add considerable value to such studies. The utility of genetic information is based on the observation that there is variability in the allele form of individual genes that can be measured and that can con- tribute to variability in health-related outcomes. Potential uses include investigation of genes that have well-established influences, such as the Apolipoprotein E (ApoE) gene and its relationship to risk for Alzheimer disease and cardiovascular disease; identification of genes that had not been previously known to have relationships with the outcome variables; investigation of whether an individualâs genetic status contributes to variability in the way in which other factors influence outcome variables (gene-environment interaction or gene-gene interaction); investigation of correlations between genetic and environmental factors; and other, more novel uses, such as controlling for genetic status to obtain a more accurate picture of how nongenetic factors are related to the outcome variables. For example, by controlling for genetic status at the ApoE gene, a clearer picture could emerge of the effect of other factors, such as cognitive activ- ity, on the development of dementia. COMPLEXITY OF THE COACTION OF GENES AND ENVIRONMENT A central question is whether the complexity of the kinds of outcome variables that are considered in social science survey research is too great to be meaningfully considered in a genetic context. This argument might be considered to be valid if one is limited to the Mendelian perspective, which is the notion that genetic influences on a trait consist of the effect of a single major gene. Much early genetics research was concerned with determining the applicability of the Mendelian rules of transmission to an ever-broadening range of phenotypes. The phenotypes were typically dichotomous (presence or absence of a disease condition is a common type of Mendelian trait), and the principal concern was whether the rela- tive numbers of organisms that were assignable to the different categories conformed to expectations derived from the Mendelian theory. Frequency
196 BIOSOCIAL SURVEYS statistics were adequate to assess the outcomes. If category assignment was reasonably unambiguous, variability in the phenotype within the categories was usually ignorable, along with any influence on that vari- ability due to environmental factors or to genes other than the primary one under investigation. The Mendelian perspective dominated medical genetics through much of the middle of the 20th century, when major progress was made in identifying single major genes that influenced a variety of medical conditions, usually devastating but rare diseases (National Center for Biotechnology Information, 2006). A parallel avenue of research into heredity was that of biometric or quantitative genetics, which was explicitly concerned with pheno- types that were continuously distributed. The analytical statistics in this approach concerned means, variances, and covariances, and the vari- ance decomposition algorithms provided for a component assignable to heredity, another to environment, and others to correlations and interac- tions between these agencies. It is this perspective that is most likely to be the more appropriate one for considering the nature of genetic effects on complex traits that are of interest in social science survey studies. It is interesting to note that there has been a substantial emphasis on the analysis of complex traits in the recent genetic literature. This approach is applied widely in psychiatric genetics, behavioral genetics, and genetic epidemiological investigations of complex health-related factors, such as risk factors for cardiovascular disease. For historical reasons that cannot be detailed here, in certain scien- tific circles, heredity, under the label of ânature,â came to be regarded as antagonistic or oppositional to environment, labeled ânurture.â The antagonism of these terms was already implied in the presumed source, Shakespeareâs âThe Tempest,â wherein Caliban is described as âa devil, a born devil, on whose nature nurture can never stick.â Galton (1883) brought the alliteration of nature-nurture into scientific discourse with the same intimation of hostility. Although his perspective was considerably more nuanced, his statement in respect to human faculty that âthere is no escape from the conclusion that nature prevails enormously over nurtureâ was easily translated into a view of nature versus nurture. This percep- tion had significant influence in the behavioral and social sciences, and led to a strong predilection to seek explanations from the environmental realm. Indeed, in some arenas, there was strong a priori rejection of any possibility of genetic involvement. In recent decades, however, a more balanced view has emerged, partaking increasingly of the quantitative genetics perspective attributing main effects to factors from both genetic and environmental domains, and with all of the subtle possibilities arising from the inevitable interaction terms. In its simplest version, the model can conceive of causal influences arising from these separate domains
GEORGE P. VOGLER and GERALD E. MCCLEARN 197 and combining additively to produce the phenotype. But it is increasingly clear that the causal relationships can be much more complex than this, with significant correlations and interactions between nature and nurture. These coactions have substantial implications for the design and interpre- tation of laboratory and field studies on health-related phenomena (see Moffitt, Caspi, and Rutter, 2005; Plomin and Rutter, 1998). Plomin, DeFries, and Loehlin (1977) provided a now-classic descrip- tion and terminology for various types of correlations and interactions in the context of behavioral genetics. Gene-environment correlations occur when the distribution of environmental influences on a particular pheno- type is not independent of the distribution of genetic influences on that phenotype. Three classes are distinguished: passive, reactive, and active. A frequently cited example of the passive situation is the provision to children of an intellectually stimulating environment of books, education, and approbation of scholarly pursuits by parents who have also transmit- ted genes that positively affect cognitive abilities. Reactive correlation arises from situations in which the (genetically influenced) behavior of an individual evokes a particular response from the social environment that tends to support (or inhibit, as the case may be) that behavior. Active correlation ensues when an individual seeks out or alters her or his envi- ronment to be consistent with a genetically influenced predilection. Various sorts of gene-by-environment (GÃE) interaction can also be identified (see, for example, Kearsey and Pooni, 1996). In general terms, however, a compact definition can encompass those circumstances in which the effect of a difference in genotype (single gene or polygenic set) depends on features of the environment or, equivalently, in which the effect of differences in features of the environment are dependent on genotype. The quantitative genetic perspective has been transformed by the wide availability of information about measured polymorphisms from DNA. This can be in the form of measurable polymorphisms in functional genes or as information on massive numbers of polymorphic markers distributed throughout the genome that are not necessarily functional polymorphisms in genes that affect the trait. The incorporation of mea- sured genetic variability has the potential to increase greatly the ability to investigate complex traits, including a genetic perspective, particularly with respect to GÃE interactions and other approaches that go beyond the idea of a main effect of an individual gene on a trait. By virtue of the degree of control that can be exercised in experimen- tal studies with animal models, GÃE interactions can be displayed with striking clarity. Because these provide illustrations of the type of interac- tive phenomena that might also be expected in human studies, we present here some examples to illustrate the phenomena.
198 BIOSOCIAL SURVEYS Animal Model Studies Some interactions have emerged from studies in which the environ- mental differences were in effect for a sustained period of time. Blizard and Randt (1974), for example, reared two inbred strains of mice under one of three housing conditionsâstandard caging and relatively enriched or impoverished in terms of sensory stimulation. (The animals of an inbred strain are approximately uniform genetically, and different inbred strains differ genetically from each other). The measured phenotype, novel object-oriented activity, was an assessment of exploratory or anxi- ety behavior exhibited when the animals were placed in a novel environ- ment. Briefly, animals of one strain (C57BL/6) were totally unaffected by differences in rearing environment; animals of the other strain (DBA/2) displayed a strong effect, with animals from the enriched condition dis- playing twice the level of activity as the impoverished group. A possible toxic risk factor for development of Alzheimer diseaseâ aluminum in the dietâwas explored in a mouse study by Fosmire, Focht, and McClearn (1993). In each of five inbred strains, two groups were established, one being fed a normal control diet and the other a diet enriched in aluminum. The brain aluminum levels of three of the strains were unaltered by diet; one showed a trend toward increase, and one displayed a threefold increase. Falconer (see Falconer and Mackay, 1996) selectively bred mice for high or low growth from three to six weeks of age on either a standard diet, or on one for which nutritional value had been degraded by dilution with nondigestible fiber. Response to selection occurred in both condi- tions. There was thus a line of animals that grew large on the good diet and another line that grew less on that diet; another line that grew large on the poor diet and one that grew less on that diet. Testing these groups under the alternate dietary condition made possible an evaluation of the extent to which the same genes influenced growth in the two environ- ments. The genetic correlation was .66, indicating a large âoverlapâ of the genes involved, but indicating also a very substantial involvement of different genes in the two nutritional environments. A further example may be drawn from the research literature on aging. Vieira and colleagues (2000) maintained Drosophila under different environmental circumstances throughout their lives. The five environ- ments differed in the temperature of the incubator in which the animals livedâstandard control, higher than control, lower than control, a control temperature but with a heat shock administered during pupal stage, and a reduced diet in a standard temperature. Seventeen quantitative trait loci (QTLs) affecting longevity were identified. (QTLs are genes associated with the phenotype but whose location on the chromosomes is known
GEORGE P. VOGLER and GERALD E. MCCLEARN 199 only approximately.) Not one of the QTLs was uniformly influential in all environments. In several cases, the effect was detectable in one environ- ment only. For some, the allele of the QTL that was associated with longer life in one environment was associated with shorter life in another; for some the influence was shown in one sex only; for some, in one particular environment, the âincreasingâ allele in females was a âdecreasingâ allele in males. In short, all of the genetic variance was involved in genotype- environment interaction, genetic-sex interaction, or both. Human Studies A common feature of these examples is that a presumptive causal ele- ment, genetic or environmental, may have differing effect depending on the context of other environmental and genetic elements that are present. Paraphrasing in terms of the health sciences, it may be expected that the virulence of risk factors and the beneficence of remedial or preventive interventions will vary greatly from individual to individual, depending on the unique context presented by each individual. As in the case of the animal model studies, we provide a sampling of the relevant literature, which is large and burgeoning. Bouchard and colleagues (1990) investigated a putative risk factorâ the effects of long-term overfeedingâin young adult male monozygotic twins. For a variety of outcome variables, including gain in body weight, percentage of fat, fat mass, and estimated subcutaneous fat, the variance among pairs was about threefold the variance within pairs. This intrapair similarity is suggestive of involvement of genotype in response to this nutritional environmental intervention (shared environmental influence cannot be ruled out, however). A polymorphism in the angiotensin-converting enzyme (ACE) that is characterized by the absence (deletion) of a 287-base pair marker has been shown to be related to the response to exercise. In general, the insertion allele (presence of the 287-base pair marker) is associated with greater endurance, whereas the deletion allele is associated with greater muscular strength, although the results have been somewhat conflicting (Folland et al., 2000; Gayagay et al., 1998; Montgomery et al., 1997; Myerson et al., 2001). On the basis of these findings, the relationship of ACE to efficacy of a health-promoting behavior in the elderly was explored by Kritchevsky and colleagues (2005). The risk to septuagenarians of developing mobility limitation was studied as a function of spontaneous activity level. Over- all, those more active at baseline were less likely than those who did not exercise to incur limitations to their activity during a follow-up period. However, an interaction was present in that individuals with a particular
200 BIOSOCIAL SURVEYS genotype at this locus (designated II) benefited less than did the other two genotypes (DD or DI). A well-studied gene with respect to gene-environment interactions related to cardiovascular health is the ApoE gene. This is one of the few genes identified to date that have common variants with well docu- ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½ mented and consistent main effects on traditional social science outcomes. Numerous studies have investigated the effect of the ApoE isoform on response to dietary intervention, with inconsistent results. In a meta- analysis of a number of studies, Ordovas et al. (1995) found that the effect of the ApoE-4 showed a higher low-density lipoprotein (LDL) response than other ApoE alleles in diets that reduced total dietary fat, no dif- ference in response in diets that reduced only dietary cholesterol, and a lower LDL response in diets in which the fat saturation (but not total amount of fat) was modified, although not all studies have found this effect (e.g., LeFevre et al., 1997). A differential response of LDL, high- density lipoprotein, and triglyceride levels to diet as a function of the ApoE-2 and ApoE-4 alleles was observed in a Finnish study of children and young adults who were in a free-living situation rather than a dietary intervention study (LehtimÃ¤ki et al., 1995). Cardiovascular responsivity to mental stress has also been shown to vary as a function of the ApoE polymorphism (Ravaja et al., 1997). Another ApoE polymorphism in the geneâs promoter region (-219GâT) has been shown to affect LDL concen- trations differentially (Moreno et al., 2004) and insulin sensitivity (Moreno et al., 2005) in response to a high-fat dietary modification. Jaffee and colleagues (2005) examined conduct problems in young twins as a function of genetic risk (estimated from co-twinâs behavior) and from physical maltreatment. Maltreatment increased probability of a conduct disorder diagnosis by 2 percent in those with the lowest genetic risk and by 24 percent among children with the highest genetic risk. The intent of this discussion has been to illustrate the potential pres- ence of interactions, not to imply that they are omnipresent. There are clearly variables in both the environmental and genetic domains that have powerful main effects. But interactions may be present, and they can be subtle and powerful. One implication is that identification of a gene as the gene for some attribute must be tentative; it might be without effect or with a different effect in some environment other than that in which it is first described. Similarly, environmental influences may have greater or lesser impact, depending on the genotype of the individuals on whom they impinge. Confidence in generality of the effect will accrue with sub- sequent observations in altered contexts. An interesting issue is whether an investigation of interaction effects should be undertaken in the absence of observation of main effects. There are methodological issues that arise related to the number of tests for interactions that are possible, resulting in
GEORGE P. VOGLER and GERALD E. MCCLEARN 201 the danger that a blind search for interaction effects in the absence of main effects could lead to a serious problem of false positive results. However, this should not preclude assessment of interaction effects in the absence of main effects under any circumstance. It is possible that subsequent work could provide a line of evidence in favor of a more careful search for interactions without main effects. The example from the meta-analysis of the differential effect of dietary intervention as a function of ApoE allele status noted above is a pertinent example, in which the differential effect of the alleles were in opposite directions, depending on the precise form of the dietary intervention. In some respects and for some purposes, correlations and interactions such as we have described can be seen as vexing. A more positive view is perhaps warranted. It may well be that the interactions that appear are indications of key processes in the functioning of the complex systems mediating genetic and environmental influences on complex phenotypes. They may be signposts to particularly productive avenues of research. In summary, a genetic perspective can be incorporated into research despite the likely complexity of genetic and environmental influences and how they interact in complex ways in social science traits. By discarding the nature versus nurture perspective, researchers studying the genetics of complex traits have embraced a more interactive model. The incorpo- ration of measured genetic variability into social science survey research, which frequently has excellent environmental assessment, opens up rich new opportunities to investigate GÃE interactions in large samples, with the potential of providing a more realistic description of factors that affect social science survey outcomes. POTENTIAL ADVANTAGES AND DISADVANTAGES The potential to investigate more complex, and more realistic, models that incorporate measured genetic information into social science survey studies is a major advantage of obtaining DNA. As noted above, the complexity of the outcomes makes utilizing DNA more challenging than simply including another predictor into a regression model. Researchers involved in genetic studies of complex traits, however, have recognized this complexity and have developed methodologies to deal appropriately with it. In the past, GÃE interaction effects could be considered only in the context of latent variable models, which have extremely limited power to detect interactions. The recent explosion in the availability of measurable DNA variability through the use of DNA markers, coupled with advances in the assessment of environmental factors, opens up opportunities to make real progress in understanding these effects on complex traits. There is a danger of improperly dealing with the complexity, resulting in mis-
202 BIOSOCIAL SURVEYS leading or biased conclusions. It is therefore essential that the use of DNA is rigorously evaluated from a methodological perspective to limit the opportunities for erroneous conclusions to be drawn. Potential Advantages In addition to the broad potential advantages in making scientific progress in understanding more completely the nature of genetic and environmental factors on complex social science traits, there are several other practical advantages. One is the potential to have DNA in long- term availability. It is possible to create either immortalized cell lines that provide unlimited access to the DNA indefinitely into the future, or to extract a finite amount of DNA from a blood, cheek cell, or saliva sample for long-term storage. Consequently, there is the potential to have long- term access to DNA for research purposes not yet conceived or for use with technology not yet developed that will make more efficient use of limited samples. Timely collection of DNA can be important in survey research, particularly longitudinal research, in which attrition can result in substantial loss to follow-up of participants in later waves of assess- ment. For surveys that focus on aging-related issues, there is the more significant issue of loss due to mortality. At first glance, the issue of GÃE interactions seems to introduce an annoying degree of complexity. When an investigator is interested pri- marily in general characteristics of a population or specific subgroup, interactions do introduce an additional source of variability that can mask the primary effects that are of interest. However, if one takes a different perspective that more closely resembles that of a clinician, the ability to identify individual-level risk factors that are not constant across the group is significant. It has the potential to provide more effective individual- level prediction of outcomes based on risk factors that are unique to the individual. A related issue is that the identification of individual-level risk factors can be used to develop prospective procedures for identifying individuals who are at high risk for developing adverse outcomes. At a minimum, such individuals can be informed of their elevated risk status so that they can be monitored more closely than standard. Of potentially greater interest is the possibility of targeting interventions specifically to at-risk individuals. The significance of this approach is that while interventions might clearly have an advantage at the overall population level, indi- viduals could respond to an intervention differentially, with its being effective for some, neutral for others, and potentially even damaging to still others.
GEORGE P. VOGLER and GERALD E. MCCLEARN 203 Potential Disadvantages The incorporation of DNA collection into social science surveys has several potential disadvantages. At a practical level, there are logistical and financial constraints surrounding the process of sample collection. How severe these constraints are depends on the method of DNA col- lection and whether it is coupled with assessment of a more extensive battery of biomarker measures. If a survey is primarily conducted by mail or telephone, DNA samples of limited yield can be collected using cheek swabs that are returned through the mail. DNA can be extracted and stored for nominal cost. The drawback is that the amount of DNA is limited, and the failure rate for obtaining a useful DNA sample can be substantial. If blood is drawn, the yield and quality of the DNA improves substantially. However, this requires contact between the participant and a trained professional for the drawing of blood. If the study involves face-to-face contact, the logistical burden can be manageable, but other- wise logistical factors can be challenging. Although the costs of obtaining a DNA sample can be minimal, the cost of genotyping large numbers of individuals from large surveys can be prohibitive unless the genetic component of the study is very tightly focused (for example, limited to genotyping of the ApoE gene). Another potential disadvantage is related to the participant burden and the purpose of the study. Participants might be recruited to a survey study on the basis of their willingness to be involved in social science research. It might not be clear to participants why they are being asked to provide DNA samples for a study that has been described to them as a social science survey. If participants have been involved longitudinally in a survey, they would not have consented to providing a DNA sample, so additional consent would be required. A request for DNA potentially imposes an additional response burden that participants had not antici- pated. If the purpose and procedures for collecting DNA are not thor- oughly and properly planned, there is the potential to introduce a bias into the sample that is related to willingness to provide DNA and not related to the primary purpose of the study. An issue that is not so much a disadvantage but a challenge involves the difficulties that arise when there is a large amount of data generated, in terms of potential type 1 and type 2 error rates and the practical issues that arise in trying to limit the number of statistical tests that are done and account for multiple comparisons. If a study opts to do a full genome scan using single-nucleotide polymorphisms (SNPs) assayed using DNA microchips, there is the potential to generate a million or more DNA markers. Dealing with such massive amounts of data requires special- ized techniques in data reduction and haplotype block identification.
204 BIOSOCIAL SURVEYS Substantial methodological work in statistical genetics is currently being conducted to address this issue effectively. ETHICAL ISSUES In addition to the more practical issues discussed above, incorpo- ration of DNA collection raises a number of ethical issues (reviewed by Durfy, 2001, in the context of aging-related surveys). Ownership of genetic information is an area that is potentially troublesome, and issues regarding ownership need to be worked out explicitly. Some studies have a policy that requires all information be made publicly available to any investigator who desires access. Other studies involving private biotech- nology companies consider the genetic information to be proprietary. It is important for issues of ownership to be clearly planned, and informa- tion regarding ownership should be made clear to the participants in the informed consent process. In addition to access issues, it is important to have a clear plan for the use that will be made of the genetic data, and these issues should be incorporated into the informed consent process. Questions regarding use include whether the use of DNA goes beyond the initial scientific goals of the survey study, whether the data will be made available to other inves- tigators outside the scope of the original project, whether the data will be retained indefinitely so that use in the future cannot be anticipated, and whether results of DNA testing will be provided back to the participant. The last issue is important, since there are few genetic results that are clear-cut risk factors for individuals, particularly in the context of com- plex traits. In the context of other modifying environmental and genetic factors, individual-level information on even well-known risk factors can be difficult to convey accurately to participants, since risk is generally reported in probabilistic terms. If the decision is to provide information to participants, considerable attention must be paid to how the information is presented. Conversely, if there is clear information about a risk factor, the investigators must consider their obligations to provide this informa- tion to participants, either now or if future work clarifies the nature of a genetic risk factor. While there are important issues regarding privacy and maintaining anonymity with public data sets for any potential identifying informa- tion, including demographic factors, these issues merit special attention for genetic data, which contain the risks associated with sensitive medical data in general but also have additional risks. Depending on the extent to which genotyping is undertaken, genetic data can contain sufficient information to identify an individual uniquely. There also is a component of risk related to the familial nature of genetic data in which there is the
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