Running Head: ANOREXIA NERVOSA: GENES and ENVIRONMENT

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Anorexia Nervosa

Running head: ANOREXIA NERVOSA: GENES AND ENVIRONMENT

Anorexia Nervosa: Genetic Components and Environmental Factors Influencing Phenotypic Expression

Nicole M. Elsasser

CreightonUniversity

Anorexia Nervosa: Genetic Components and Environmental Factors Influencing Phenotypic Expression

An anonymous poem, Footprints in the Sand, concludes with the following powerful words: “The LORD replied, “My precious, precious child, I love you and I would never leave you. During your times of trial and suffering, when you see only one set of footprints, it was then that I carried you.” During my recovery from a three year battle with anorexia nervosa- restricting type, these words carried me through the most difficult part of recovery. Suffering from a devastating illness that had controlled me for three years, taken away my personality and hope, hurt the people I most cherished in life, and left my body struggling to hold on, I needed to completely surrender myself to something outside of myself to begin to recover. Anorexia nervosa is a serious life-threatening disorder that increasingly affects mothers, daughters, sisters, aunts, cousins, friends, teachers and many more each and every day. Males also suffer from this disorder, though the prevalence is extremely rare in men and has a small research base (Woodside, Garner, Rockert, & Garfinkel, 1990, pp.100;113). While the environmental causes of anorexia nervosa have received a great deal of attention in the past, genetic research shows a promising avenue to pursue better treatment options for this complicated disorder. Twin studies as well as specific gene studies on the norepinephrine transporter and the estrogen receptor 2 genes have all confirmed a genetic susceptibility to anorexia that increases an individual’s risk of phenotypically expressing the disorder (Bulik, Sullivan, Wade, & Kendler, 1999; Urwin et al., 2002; Eastwood, Brown, Markovic, and Pieri, 2002). As anorexia nervosa is an extremely complex disorder that is known to have significant environmental factors influencing phenotypic manifestation, the emerging research on the genetic components to the disorder generate enormous promise in developing effective treatments.

Background Information

History of Anorexia Nervosa

In Solving the Anorexia Puzzle: A Scientific Approach, Epling and Pierce (1992) take an evolutionary look at anorexia nervosa, stating that “activity anorexia is a natural response to unexpected food shortage” (p. 164). Thus, the process of natural selection favored individuals who could travel to other locations when food was scarce and who were able to become anorexic during that time.Animals start to eat when the value of travel is no longer reinforced by food shortage, that is, when food density increases (Epling & Pierce, 1992). However, in a post-industrial revolution society, anorexia nervosa is no longer a beneficial response to food shortage. In fact, it is now a complex and devastating psychological disorder for those who suffer from it directly as well as for their families and loved ones.

Current Definition and Prevalence

According to The American Psychiatric Press Textbook of Psychiatry, “anorexia nervosa is a disorder characterized by preoccupation with body weight and food, behavior directed toward losing weight, peculiar patterns of handling food, weight loss, intense fear of gaining weight, disturbance of body image, and amenorrhea” (Hales, Yudofsky, & Talbott 1994, p. 859). Furthermore, one subtype of anorexia nervosa that will be discussed is restricting type. It is characterized by the DSM-IV as “during the episode of anorexia nervosa, the person has not regularly engaged in binge-eating or purging behavior (i.e., self-induced vomiting or the misuse of laxatives, diuretics, or enemas)” (Hales et al., 1994, p. 859).

Furthermore, though anorexia nervosa is known to affect less than 1% of the general population, “the incidence of anorexia nervosa has increased in the past 30 years in both the United States and in Western Europe” (Hales et al., 1994, p. 860). Moreover, anorexia is a disorder in which the vast majority of patients are female. Estimates vary from 90% to 96% of all suffers to be female. In terms of prevalence and long-term outcomes of anorexia, the following shows the seriousness of the disorder:

The course of anorexia nervosa varies from a single episode with weight and psychological recovery, to nutritional rehabilitation with lapses, to an unremitting course resulting in death. Two of the most methodologically satisfying long-term follow-up studies have shown a death rate of 6.6% at 10 years after a well-defined treatment program and a death rate of 18% at 30 year follow-up. (Hales, Yudofsky, & Talbott, 1994, p. 861)

Clearly, anorexia is a serious and life-threatening disorder that dramatically affects the quality of life of an individual. Even after well-defined treatment programs have been followed, the risk to an anorexic individual is great. Hales et al. (1994) also found that “longer duration of illness, older age at onset, previous admissions to psychiatric hospitals, poor childhood social adjustment, premormid personality difficulties, and disturbed relationships between patients and other family members” (p. 861) added to the risk of having a poor long-term outcome with the disorder. High quality and informed treatment programs may help to increase the possibility of full recovery from anorexia and genetic research may be key to these advancements.

Studies

Twin Studies

Twin Studies of Eating Disorders: A Review emphasizes a critical point about research concerning anorexia nervosa:

Ultimately, our understanding of eating disorders and related behaviors will be enriched by considering Gene x Environment interactions. The environmental factors that have received so much attention in eating disorder research will most likely prove to be important mediating and/or moderating factors that contribute to the expression of the disorders in genetically susceptible individuals. (Bulik et al., 1999, p.17)

This conclusion, which highlights the importance of a genetic susceptibility to anorexia nervosa, is a vital statement to the future of eating disorder research. As the quote suggests, much of the research and general information available about anorexia nervosa focuses solely on the environmental factors associated with the disorder. However, like multitudes of other diseases, there is finally some research being done to bring attention to genetic factors that may largely contribute to an individual’s phenotypic expression of anorexia nervosa. Moreover, the article asks some poignant questions that promote the idea of genetics playing a crucial role in anorexia nervosa.

If exposure to unrealistic societal expectations about body shape and weight are nearly universal (in some cultures), then why do such a small number of women develop eating disorders? It is conceivable that the degree of risk conferred to adolescent food fads, diets…only confer risk proportionately to one’s degree of genetic liability. (Bulik et al., 1999, p.17)

While no study has found genetic effects to be the sole cause of eating disorders, the question that Bulik and her colleagues pose is a perplexing problem. With a lifetime prevalence rate of 0.75% in a fast-paced environment that worships thinness and perfection, there must be something about the nature or genetics of an individual that puts him or her at a much higher risk for developing anorexia nervosa than the average individual. Accordingly, several studies have pointed in the direction of a heritability factor for anorexia nervosa.

Comparative twin studies of MZ and DZ twins, population-based samples, between anorexia and major depression have all suggested a genetic component to the disorder. In fact, “the first systematic study of clinically ascertained twins with AN [Anorexia Nervosa] found that the concordance for MZ twins was substantially greater than for DZ twins…[where] the observed aggregation appeared to be mostly influenced by additive genetic affects” (Bulik et al., 1999, p.10). Thus, even with a shared environment, MZ twins were found to have much more parallel development of anorexia nervosa than their DZ counterparts, suggesting that genetic differences may be a strong determinant in the phenotypic expression of anorexia nervosa. Similarly, when compared to a population-based sample, the concordance rates in MZ and DZ twins were found to be 10% and 22%. However, such studies are few and far between; when Twin Studies of Eating Disorders: A Review was published in 1999, only two published studies had investigated genetic and environmental contributions to the causes of the disorder in a population-based sample. Generally speaking, the rarity of anorexia nervosa has made it difficult to reach conclusions about the genetic and environmental factors contributing to the causes of the disorder. Still, in a bivariate analysis of anorexia and major depression, “the heritability of anorexia was estimated to be 58% and there was correlated genetic liability between anorexia and major depression” (Bulik et al., 1999, p.10). So, despite its rarity, some important findings about the heritability and possible genetic patterns of anorexia nervosa have been supported by research. As Bulik and her colleagues summarize, “from these twin and family studies, we can conclude that anorexia nervosa is familial; however, the resolution of the nature of the familiarity will require larger sample sizes or alternative strategies”(Bulik et al., 1999, p.10). Fortunately, more recent studies, which focus on specific genes that increase an individual’s risk of developing anorexia nervosa, have clarified some of the genetic causes behind the disorder’s familial nature.

Studies of Genetic Susceptibility

Two significant studies have been done within the past two years that show motivating evidence that there may be specific genetic qualities that predispose an individual to phenotypically express anorexia nervosa (Eastwood et al., 2002; Urwin et al., 2002). First of all, Urwin et al. (2002) conducted a collaborative study in Australiahas found evidence in the norepinephrine transporter (NET) gene. Moreover, a second study of 170 British Caucasian anorexic females by Eastwood et al. (2002) suggests that the variability in the estrogen receptor 2 gene (ESR2) alone may contribute to the genetic susceptibility to anorexia nervosa

The first study, conducted with 87 Australian trios (patient plus parents), began on the evidence that “long-term weight-restored patients with anorexia nervosa (AN) have lower norepinephrine levels than controls” (Urwin et al., 2002, p.652). Because these lowered levels could reflect an altered reuptake by the NET gene, the experimenters correctly hypothesized that the NET gene was a genetic cause of AN. During the course of the study, the subject trios “demonstrated a significant preferential transmission of L4 from parent to child with restricting AN (AN-R), suggesting that L4 or a DNA variant inlinkage disequilibrium with it, doubles the risk for developing AN-R” (Urwin et al., 2002, p.652). L4 refers to a 4-bp insertion into a portion of the NET gene promoter region, which results in a net gain in potential Elk-1 sites.Although the genetic specifics of this study are complex, the conclusions it has revealed are of great consequence.

Conclusions of the NET gene study are striking and have phenomenal implications. First, Urwin et al. (2002) found that due to the L4 variant being involved in the disease process or being in linkage disequilibrium withit,the restrictive subtype of anorexia nervosa is conclusively associated with L4. Thus, a specific genetic correlation has been found between anorexia and genetic variations. Such evidence opens a world of possibility into the diagnostic procedures and risk education as it relates to anorexia in families. Because this study used both patients and their parents as test subjects, it is reasonable to hypothesize that a genetic test could be developed in the near future to detect the transmission of L4 from parents to offspring.Because Urwin et al. (2002) noted that L4 doubles the risk for developing anorexia, such a genetic test could be crucial to figuring out how to keep such a genotypic predisposition from manifesting in phenotypic expression. Staying true to the importance of environmental factors, as discussed above, it may be possible to structure the environment of a predisposed individual in such a way as to significantly lower his or her risk of expressing the disorder. For example, equipped with his or her unique genetic information and family history, a genetically susceptible individual may take special precautions such as becoming educated about the disorder, refraining from dieting, working on maintaining a healthy body image, or limiting their exposure to media glorification of weight loss and thinness.Furthermore, as “premorbidly, AN patients often have anxiety disorders” (Urwin et al., 2002, 655), creating balanced approaches to success and taking preventative measures to reduce anxiety may keep an individual who is predisposed to AN-R from ever phenotypically demonstrating the life-changing disorder.

A second study, much different in nature from the NET gene trio study, looked at the genetic role of estrogen in the development of anorexia nervosa. Comparing a group of 170 female, Caucasian AN sufferers to 152 female controls, Eastwood et al. (2002) were looking to find some genetic evidence that demonstrated that 90% of all AN sufferers are female. While, superficially, the images of thin women in the media are often thought to contribute to the prevalence of the disorder manifesting in females, this study went inside the genetic make-up of the individual to search for answers. What they found was that the estrogen receptor 2 gene (ESR2) plays a critical role in the development of anorexia nervosa. Eastwood et al. (2002) based their study on the information that “estrogen receptors have been localized to areas of the brain involved in behavior and regulation of food intake” (Eastwood et al., 2002, p. 86). Furthermore, “the anorexic effects of estrogen are accentuated by stress” (Eastwood et al., 2002, p. 86). Thus, the researchers correctly hypothesized that variation in estrogen receptors may cause genetic predisposition for the disorder.

The unique aspect of this particular genetic study is that it focuses on the female in relationship to anorexia nervosa. Because the gender differences in the manifestation of the disorder are so unbalanced, this approach of looking at hormonal differences between males and females as the genetic culprit to AN susceptibility is intriguing. Eastwood et al.’s article duly notes that “it is generally accepted that the age of onset of AN shows a biomedical distribution with one peak at or around the age of puberty in females when estrogen levels are dramatically increased”(Eastwood et al., 2002, p. 86). Likewise, “in rodents and primates high estrogen levels are known to have an inhibitory effect on food intake” (Eastwood et al., 2002, p. 86). Clearly, there seems to be some connection between the female hormone, estrogen, and the phenotypic expression of anorexia. Not only does this relationship suggest a genetic cause of AN, but it also offers some answers to the problem of gender differences in the disorder. Moreover, brain structure as it interacts with estrogen and corticotrophin releasing factor (CRF)² are shown to modify the hypothalamic pituitary adrenal (HPA) axis (Eastwood et al., 2002). What’s more, “the disruption of the HPA axis in AN suffers cannot be wholly attributed to the effects of semi-starvation and the HPA axis is also elevated in response to stress” (Eastwood et al., 2002, p. 86). Clearly, this study offers a great deal of reasonable and convincing evidence that the female hormone may be largely responsible for gender differences in the brain, not attributable to starvation, which create a biological environment within the female body that is more susceptible to anorexia then their male counterparts. In relation to specific estrogen receptors, “variants of the ESR1 gene have been implicated with anxiety…[and] it has previously been suggested that anxiety may accentuate the anorexic effects of estrogen” (Eastwood, et al., 2002, p. 86). As stated above, the majority of AN sufferers also suffer from anxiety, so finding a hormonal connection between estrogen and anxiety is key.

Yet, the results of this study were not as conclusive as the findings in the first study involving the NET gene. Eastwood et al. (2002) found that “in the present study there is no evidence of variation at the ESR1 locus contributing to the genetic susceptibility to AN” (p. 87). Similarly, “construction of haplotypes of ESR1 and ESR2 does not suggest any interaction between these two loci in the pathology of anorexia nervosa” (Eastwood, et al., 2002, p. 87). Thus, evidence confirms that ESR1 and ESR2 do not work together to increase an individual’s predisposition to AN. However, “variability in ESR2 alone may contribute to the genetic susceptibility to AN” (Eastwood et al., 2002, p. 86). So, while the gene that affects anxiety is not to be directly related to causing anorexia, another estrogen receptor may hold the key to why females are much more prone to AN than males. While it seems likely that a disorder that involves such a high level of anxiety would have a genetic link to anxiety, the research has not been conclusive in this arena thus far.Still, the genetic findings of this study are encouraging, including its report of “an association with the heterozygous genotype G1082A…[and] observed an increase frequency of the 1082A allele in the AN population which results in the genotype frequencies in this population alone”(Eastwood et al., 2002, p. 87). Therefore, a specific genetic variation was found in great prevalence among AN women. Differing in their genetic make-up in a specific way from the control population is a hopeful step in isolating genes that cause anorexia. Finally, the role of estrogen in the form of ESR2 cannot be excluded in the susceptibility of AN, though further research is needed to strengthen the conclusiveness of its role in the disorder (Eastwood et al., 2002).

Considering Males

With such an intense focus on the female experience of anorexia nervosa, it is important to remember that there are males who also experience this disorder, even though they represent a small minority of sufferers. In Males with Eating Disorders, Woodside et al. (1990) compare the demographic and clinical features of males and females with anorexia nervosa. Notably, their research found that “compared to a larger group of females with similar diagnoses, there are no significant between group differences on age of presentation, duration of illness, or weight at presentation” (Woodside et al., 1990, p. 106). Of particular interest is the similarities between males and females in the age of onset for AN. In the afore-mentioned study with estrogen, one of the bases of the study was the peak in the prevalence of anorexia in girls at or around the time of puberty, when estrogen levels increase dramatically. However, this research comparing males and females with the disorder seems to negate this relationship because men do not have that same peak in estrogen levels, but tend to develop anorexia at a similar age as women.Additionally, “it may be concluded that anorexia nervosa…[is] more alike than dissimilar in males and females, and that the differences in the indices of psychopathology are generally not indicative of differences in process” (Woodside et al., 1990, p. 113). Therefore, it seems reasonable to gather that the genetic predisposition to anorexia cannot completely rest in genetic gender differences. Still, this study also emphasizes the great need for larger samples and more studies to look at the male experience of AN. Again, the rarity of the disorder, especially in males, has limited the quality and quantity of information available about this complicated disorder.