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Handbook of Eating Disorders and Obesity
John Wiley & SonsISBN: 0-471-23073-1
Chapter OneGENETIC AND BIOLOGICAL RISK FACTORS
CYNTHIA M. BULIK
THE "OLD BIOLOGY OF EATING DISORDERS"
Historically, sociocultural and family theories of etiology have dominated the scientific literature on eating disorders. There was certain sound logic to the belief that the pervasive emphasis on thinness as a symbol of beauty and control somehow "caused" eating disorders or that certain family interaction patterns were more likely than others to bring food and eating-related issues to the fore as a center of familial conflict. These explanations had considerable face validity-they seemed like common sense. However, they were not rigorously tested as true prospective risk factors. For decades, biological researchers have been working in the background of the scientific community of eating disorders. A small but dedicated group of researchers has continued to forge ahead with the notion that biology plays a substantial causal role in the etiology of anorexia nervosa (AN) and bulimia nervosa (BN).
THE "NEW BIOLOGY OF EATING DISORDERS"
In the past decade, genetic and biological research has moved to the forefront of our expanding knowledge about eating disorders. The findings are not ignorable, and they are forcing each of us to reshape our conceptualization of these disorders. Components of the "new biology" include research in the areas of epidemiology, genetic epidemiology, molecular genetics,neurobiology of feeding, neurobiology of eating disorders, genetics of obesity and thinness, and neuroimaging studies. In this chapter, I address how research on genetic epidemiology and genetics of eating disorders is forcing us to refocus our understanding of the balance of the contributions of genetic and environmental factors to the etiology of anorexia nervosa and bulimia nervosa.
HOW HAS GENETIC EPIDEMIOLOGY CHANGED OUR UNDERSTANDING OF THE ETIOLOGY OF EATING DISORDERS?
Over the past decade, a burgeoning of family, twin, and molecular genetic studies of eating disorders has shed new light on etiological factors associated with AN and BN. These findings have been sufficiently strong and adequately replicated to warrant the recommendation that all individuals in the field consider developing at least a passing familiarity with their meaning and their implications for etiology, prevention, and treatment of eating disorders. This chapter outlines the background for understanding the genetic epidemiological and molecular genetic approaches, presents current findings relevant to eating disorders, and suggests implications for prevention and treatment.
The Methods of Genetic Epidemiology: Family, Twin, and Adoption Studies
Three major research designs in genetic epidemiology allow for the delineation and quantification of the relative contribution of genes and environment to the etiology of complex behavioral traits (see Table 1.1). The first step is to determine whether a trait or disorder aggregates in families. This question can be addressed by the traditional family study, which determines whether there is a statistically greater lifetime risk of eating disorders in biological relatives of individuals who have an eating disorder in comparison to relatives of individuals without eating disorders. If no increased risk is observed, probability that the disorder is genetically influenced is low. The primary limitation of the family design is that genetics and environment are confounded. Therefore, if you find that a disorder or trait runs in families, the family study does not allow you to determine to what extent that familial pattern is due to genes and to what extent it is due to environment.
Two additional designs are possible that enable the disentangling of genetic and environmental effects, namely adoption and twin designs. Adoption studies are a social experiment in which the degree of similarity between an adoptee and his or her biological versus adoptive parents is compared. A greater similarity to biological parents suggests genetic effects, whereas greater similarity to adoptive parents suggests environmental effects. Although these are powerful designs, adoption is rare and the method is complicated by a number of assumptions. Moreover, when studying rare complex traits such as eating disorders, prevalence of the disorders is often too low to draw meaningful conclusions from adoption studies.
Twin studies, in contrast, are a biological experiment. Monozygotic (MZ) or identical twinning occurs at some stage in the first two weeks after the first mitosis when the zygote separates and yields two genetically identical embryos. Therefore, any differences between MZ twins who-for most intents and purposes share all of their genes-provide strong evidence for the role of environmental influences (Plomin, DeFries, McClearn, & Rutter, 1994, pp. 171-172). Dizygotic (DZ) or fraternal twinning results from the fertilization of two ova by different spermatozoa. DZ twins are no more similar genetically than nontwin siblings and share-on average-half of their genes identical by descent. Thus, differences between DZ twins can result from genetic and/or environmental effects.
The goal of the classical twin study is to use the similarities and differences between MZ and DZ twin pairs to identify and delineate genetic and environmental causes for a particular trait. Twin studies are one of the few quasi-experimental means to accomplish this goal in humans and are often the only practical approach.
Using structural equation modeling techniques, liability can be parsed to a trait or disorder into three sources of variability: additive genetic effects ([a.sup.2]), common or shared environmental effects ([c.sup.2]), and unique environmental effects ([e.sup.2]).
Additive Genetic Effects (Abbreviation A)
Although a number of different types of genetic influences can be studied in theory (e.g., dominance or epistatic effects), statistical power is usually low except for additive genetic effects (Neale, Eaves, & Kendler, 1994). Additive genetic effects result from the cumulative impact of many individual genes, each of small effect. The presence of A is inferred when the correlation between MZ twins is greater than the correlation between DZ twins. If a trait were entirely due to additive genetic effects and could be measured without error, the MZ_DZ correlation would be 1.0 and 0.5, respectively.
Common Environmental Effects (Abbreviation C)
Common environmental effects result from etiological influences to which both members of a twin pair are exposed regardless of zygosity. Thus, common environmental effects contribute equally to the correlation between MZ and between DZ twins. In the simplest case, if the correlations between MZ and DZ twins are both 1, the trait is entirely determined by common environmental effects. Examples include the social class and religious preference of the family of origin.
Individual-Specific Environmental Effects (Abbreviation E)
The second type of environmental effect results from etiological influences to which one member of a twin pair is exposed but not the other. Thus, individual-specific environmental effects decrease the magnitude of the correlation between both MZ and DZ twins. In the simplest case, if the correlation between both MZ and DZ twins is 0, the trait is entirely determined by individual-specific environmental effects. Examples include one member of a twin pair being exposed to a traumatic experience not shared with the co-twin.
Qualitative characterizations such as the presence of C or the absence of A are useful, but quantifying the contributions of A, C, and E is more relevant. It is straightforward to scale the total variance of a trait to one and to use twin pair correlations to describe the proportions of variance due to A, C, and E. The proportion of variance due to A (additive genetic effects) is [a.sup.2] (also known as heritability or, more correctly, as narrow heritability in liability). The proportion of variance due to C is [c.sup.2], and the proportion due to E is [e.sup.2]. The value of [e.sup.2] also incorporates measurement error. The values of [a.sup.2], [c.sup.2], and [e.sup.2] must sum to the total variance of one.
What Is Heritability? What Isn't Heritability?
Perhaps because of unfamiliarity with the approach, twin studies can easily be misinterpreted. Heritability estimates are often quoted with little understanding of their meaning or of their limitations. Most importantly, there is not one true heritability estimate for any given trait or disorder. Heritability is a statistic that varies across populations and across time. Perhaps one of the most vivid examples of how heritability estimates of a trait can change over time emanates from a study of smoking behavior in male and female twins in Sweden. Kendler, Thornton, and Pedersen (2000) explored the pattern of twin resemblance for regular tobacco use in a population-based sample of Swedish twins. Results for males suggested both genetic and rearing-environmental effects, which, in the best-fit biometrical model, accounted for 61% and 20% of the variance in liability to regular tobacco use, respectively. For women, the pattern differed by birth cohort. In women born before 1925, rates of regular tobacco use were low and twin resemblance was influenced primarily by environmental factors. In later cohorts, rates of regular tobacco use in women increased substantially and heritability estimates were on par with those seen in men (63%). This study shows that heritable influences were detectable in females only after social constraints on female tobacco use were relaxed.
Allison and Faith (2000) outline a number of common misinterpretations of heritability. For example, a heritability of BN of 83% does not mean that 83% of the reason that people develop bulimia is genetic or that 83% of the people who have bulimia have a "genetic form" of bulimia. What it does mean is that approximately 80% (probably, more likely, 50% to 85% considering the confidence intervals) of the variance in liability to BN is due to genetic effects. More simply, your genes play a role in determining the extent to which you are liable to develop BN (or whatever the relevant trait may be).
LINKAGE AND ASSOCIATION STUDIES
If genetic effects appear to be important in the transmission of the disorder, linkage and association studies are next employed to determine the precise location, identity, and function of the genes that are implicated.
The two prominent molecular genetic designs are case-control association studies and linkage studies (Sham, 1998; Table 1.2). Case-control association studies are often viewed as alternative or complementary to linkage studies, which have yet to be as richly fruitful in the study of complex psychiatric traits in neuropsychiatry as they have with Mendelian disorders (Moldin, 1997; Risch & Zhang, 1996). Linkage studies (Craddock & Owen, 1996; Lander & Schork, 1994; Ott, 1991; Sham, 1998; Terwilliger & Goring, 2000) investigate correlations between a disease and inheritance of specific chromosomal regions in families, whereas association studies focus on differences in the frequency of specific genetic markers in groups of affected versus unaffected individuals (see Table 1.2).
The standard approach to association studies is to ascertain cases with a trait of interest and controls without the trait, obtain DNA samples, and genotype all subjects for a genetic marker believed to be of etiological relevance. Statistical analysis compares allele or genotype frequencies (Sasieni, 1997) in cases versus controls (Sham, 1998). As with any case-control approach, there are numerous sources of bias (Sackett, 1979); considerable care must be taken to ensure the proper matching of cases and controls. Fundamentally, cases and controls should represent "identical" samples from a single population except for the diagnostic differences. Confidence in case-control association studies wavers (Crowe, 1993; Gambaro, Anglani, & D'Angelo, 2000; Kidd, 1993; Risch & Zhang, 1996; Sullivan, Eaves, Kendler, & Neale, 2001). Association designs are particularly useful and powerful when prior knowledge of the pathophysiology of a trait suggests a number of candidate genes. However, the use of this design is controversial because of the risk of false positive findings when studying a sample that contains individuals of evolutionary diverse ancestry (Kidd, 1993). More often than not, seemingly exciting findings from association studies in neuropsychiatry are followed rapidly by a series of nonreplications (Moldin, 1997; Risch & Zhang, 1996; Stoltenberg & Burmeister, 2000).
Linkage studies can be used in gene discovery with a sufficiently large number of multiplex pedigrees or extreme sibling pairs (Allison, Heo, Schork, Wong, & Elston, 1998). Anonymous genetic markers scattered across the genome can identify the chromosomal regions that may contain genes that contribute to the trait of interest. The strength of this design is tempered by the relatively low power (Risch & Merikangas, 1996) and resolution (Roberts, MacLean, Neale, Eaves, & Kendler, 1999) likely for linkage studies of complex traits. Given the size of the human genome, linkage studies allow narrowing down of regions of interest for a particular trait. Results of linkage studies can then be applied to the choice of rational candidate genes for association studies. The choice of candidate genes can then be based on function requiring knowledge of the function of the genes and proposed pathophysiology of the traits, as well as position (gene is located under the observed linkage peak).
Both association and linkage designs have been applied to the study of eating disorders, although genetic studies in the field are truly in their infancy.
APPLICATION OF GENETIC EPIDEMIOLOGY AND MOLECULAR GENETICS TO EATING DISORDERS
Family Studies of Eating Disorders
A series of large, well-controlled family studies of eating disorders now exists. The vast majority of controlled family studies (Gershon et al., 1983; Hudson, Pope, Jonas, Yurgelun-Todd, & Frankenburg, 1987; Kassett et al., 1989; Lilenfeld et al., 1998; Strober, Freeman, Lampert, Diamond, & Kaye, 2000; Strober, Lampert, Morrell, Burroughs, & Jacobs, 1990) have found a significantly greater lifetime prevalence of eating disorders among relatives of eating-disordered individuals in comparison to relatives of controls. Moreover, several studies have found increased rates of both AN and BN (i.e., coaggregation) in relatives of individuals with AN as well as individuals with BN, compared to rates among relatives of controls (Gershon et al., 1983; Hudson et al., 1987; Kassett et al., 1989; Strober et al., 1990, 2000), suggesting that AN and BN share transmissible risk factors.
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Table of ContentsPreface.
PART I. EATING DISORDERS: ANOREXIA NERVOSA, BULIMIA NERVOSA, AND BINGE EATING DISORDER.
SECTION 1. ETIOLOGY, RISK, AND PREVENTION.
Chapter 1. Genetic and Biological Risk Factors (Cynthia M. Bulik).
Chapter 2. Risk Factors for Eating Disorders: An Evauation of the Evidence (Alison E. Field).
Chapter 3. Eating Disorder Prevention Programs (Eric Stice & Emily Hoffman).
SECTION 2. ASSESSMENT AND DIAGNOSIS.
Chapter 4. Diagnosis and Classification of Eating Disorders (Debra L. Franko, et al.).
Chapter 5. Assessment of Medical Status and Physical Factors (Claire Pomeroy).
Chapter 6. Psychological Assessment of Eating Disorders and Related Features (Drew A. Anderson and Caroline A. Paulosky).
SECTION 3. TREATMENT.
Chapter 7. Cognitive-Behavioral Therapy in the Treatment of Anorexia Nervosa, Bulimia Nervosa and Binge Eating Disorder (Kathleen Pike, et al.).
Chapter 8. Interpersonal Psychotherapy for the Treatment of Anorexia Nervosa, Bulimia Nervosa, and Binge Eating Disorder (Stacey Tantleff-Dunn, et al.).
Chapter 9. Pharmacological Treatment of Anorexia Nervosa, Bulimia Nervosa, and Binge Eating Disorder (Martina de Zwaan, et al.).
Chapter 10. Family Approaches for Anorexia Nervosa and Bulimia Nervosa (James Lock).
Chapter 11. Dialectical Behavior Therapy for Eating Disorders (Elizabeth Blocher McCabe, et al.).
Chapter 12. Integrative Cognitive Therapy for Bulimia Nervosa (Carol B. Peterson, et al.).
Chapter 13. Feminist Therapy and Eating Disorders (Niva Piran, et al.).
Chapter 14. Internet-Based Treatment Strategies (Andrew J. Winzelberg, et al.).
Chapter 15. Impatient and Partial Hospital Approaches to the Treatment of Eating Disorders (Angela S. Guarda and Leslie J. Heinberg).
PART II. OBESITY.
SECTION 1. ETIOLOGY, RISK, AND PREVENTION.
Chapter 16. Genetic and Biological Risk Factors (Mark B. Cope and David Allison).
Chapter 17. The Toxic Environment and Obesity: Contribution and Cure (Kathryn E. Henderson and Kelly Brownell).
Chapter 18. Psychosocial and Behavioral Consequences of Obesity (Diane Neumark-Sztainer and Jess Haines).
SECTION 2. ASSESSMENT AND DIAGNOSIS.
Chapter 19. Assessment of Medical Status and Physical Factors (M. Ammar Hatahet & Nikhil V. Dhurandhar).
Chapter 20. Behavioral Assessment of Obesity (Suzanne Phelan and Thomas A. Wadden).
SECTION 3. TREATMENT.
Chapter 21. Treatment of Obesity I: Adult Obesity (David B. Sarwer, et al.).
Chapter 22. Treatment of Obesity II: Childhood and Adolescent Obesity (Jordana Cooperberg and Myles Faith).
PART III. BODY IMAGE DISTURBANCES AND BODY DYSMORPHIC DISORDER.
Chapter 23. Risk Factors for the Development of Body Image Disturbances (Eleanor H. Wertheim, et al.).
Chapter 24. Assessment of Body Image Disturbances (Tiffany M. Stewart and Donald A. Williamson).
Chapter 25. Treatment of Body Image Disturbances (Thomas F. Cash and Joshua I. Hrabosky).
Chapter 26. Body Dysmorphic Disorder (Roberto Olivardia).
PART IV. SPECIAL TOPICS.
Chapter 27. Sociocultural Aspects of Eating Disorders (Eileen P. Anderson-Fye and Anne E. Becker).
Chapter 28. A Feminist Approach to Eating Disorders (Linda Smolak and Sarah K. Murnen).
Chapter 29. Weight and Shape Concerns of Boys and Men (Marita P. McCabe and Lina A. Ricciardelli).
Chapter 30. Eating Problems in Childhood and Adolescence (Dasha Nicholls).
Chapter 31. Obesity and Body Image in Ethnically Diverse Children and Adolescents (Sonia Y. Ruiz, et al.).
Chapter 32. Child Sexual Abuse and Eating Disorders (Kevin M. Thompson and Stephen A. Wonderlich).
Chapter 33. Media's Role in the Perpetuation and Prevention of Negative Body Image and Disorderd Eating (Michael Levine and Kristen Harrison).
Chapter 34. Cosmetic Surgery and Cosmetic Medical Treatments (David B. Sarwer, et al.).
Chapter 35. Future Directions in Eating Disorder and Obesity Research (Linda Smolak and Ruth Striegel-Moore).
What People are Saying About This
"A handbook that is intended to cover clinical research and practice in the area of eating disorders and obesity should be representative of the field, provide critical guidance, and be accessible to the nonspecialist. According to these criteria, this handbook succeeds. It accurately portrays progress and problems. In the chapters that involve science...the writing is clear and critical..." Gerard P. Smith, MD of Weill Medical College of Cornell University in the New England Journal of Medicine - Volume 351, Number 2, July 8, 2004