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What is the Relationship

Between Genetics and Anorexia?

Adrienne Dula

Anorexia Nervosa is a disorder characterized by aberrant patterns of feeding behavior and weight

regulation. The patients suffer from disturbances in attitude toward weight and shape as well as their

body image and perception of their body shape. There is an inexplicable fear of weight gain and an

unrelenting obsession of fatness, even in the face of increasing cachexia. Patients refuse to maintain

body weight over a minimal normal weight for age and height and they exhibit denial of the seriousness of

this low body weight. In post-menarcheal females, there is an absence of at least the last three of her

menstrual cycles.

Two subtypes of this disorder exist, the binge eating/purging subtype and the restricting subtype. The

patient suffering from the binge eating/purging subtype engages in recurrent episodes of binge eating or

purging behavior during the episodes of anorexia. The restricting subtype is characterized by scrupulous

restriction of food intake with the absence of the binge eating and purging episodes.

The cause of the disorder is presumed to be complex and multiply influenced by developmental, social,

and biological processes, but the exact interaction among these processes remains incompletely

understood. It is certain that cultural attitudes toward standards of physical attractiveness have

relevance to the psychopathy of eating disorders, but it is unlikely that the cultural influences in

pathogenesis are very prominent. For example, dieting behavior and striving to be thin are commonplace

in many industrialized countries but anorexia nervosa's lifetime prevalence among females is estimated

0.1% - 0.7% (Kaye, W.,2000).

In addition to this, numerous clear descriptions of anorexia date from the middle of the nineteenth

century, suggesting that factors other than our current culture have an etiologic role in the development

of the disorder (Klump, K., 2001). Anorexia has a relatively stereotypic clinical presentation, sex

distribution, and age-of-onset, which supports the possibility of some biological vulnerability, while

highlighting the fact that the genetic diathesis for eating abnormalities is likely to be highly polygenic with a

multitude of genetic traits contributing to its development (Klump, K., 2001). It has been suggested that

there may be a gradual accumulation of risk factors, which only manifest themselves during the stress of

adolescence (Karwautz, R., 2001).

These proposed risk factors appear to be both extrinsic and intrinsic. The extrinsic factors include

adverse experiences while the intrinsic focus on genetic vulnerability. They have been proposed to act

either as fundamental etiological risk factors (predisposing), as triggers for the illness (precipitating), or

to prolong and exacerbate the illness (maintaining). Due to the complexity, it is unlikely that each risk

factor can be classified in this way. Prospective studies which use a design sensitive to both genetic and

environmental factors will be the only way to clarify these issues (Karwautz, R., 2001).

Throughout the literature, a general agreement exists that the results of twin and family studies suggest a

genetic vulnerability to anorexia nervosa and model-fitting of data obtained from twin studies suggests

that non-shared factors, such as differential experiences and genes are of greater importance than

shared factors in anorexia nervosa (Karwautz, R., 2001).

Several developmental and early environmental factors seem to increase the risk of developing the

eating disorder. While the risk of pre-term birth and faddy eating in childhood have been shown to be

linked to partial cases of anorexia, parental and personal obesity, dieting in family members, and adverse

comments about weight/shape or eating were not seen to be antecedents for anorexia nervosa

(Karwautz, R., 2001). None of the risk factors implicated so far appear to be necessary or sufficient to

account for the development of anorexia nervosa. Inconsistent results highlight the need for additional

population-based twin studies to clarify findings and determine the generalizability of heritability estimates

from clinical samples (Klump, K., 2001).

Anorexia is widely assumed to have a complex, multi-factorial etiology, yet psychological theories of

pathogenesis have largely prevailed in explanatory paradigms which were presented in the recent

decades (Kaye, W.,2000). This disorder occurs frequently in association with Axis I psychiatric

disorders, mood and anxiety disorders in particular. These disorders have no evident connection to

cultural attitudes relating to body weight, and are commonly associated with biological disturbances in the

system as their cause. In addition, it has been suggested that there may be a gradual accumulation of

risk factors which only manifest themselves during the stress of adolescence (Karwautz, R., 2001) as

opposed to purely psychological causes for this disorder.

The stereotypical onset for anorexia nervosa coincides with the developmental changes which take

place during puberty. This occurrence has been hypothesized to be due to genetic relationships between

eating abnormalities and the ovarian hormones activated during puberty. A study was conducted

involving 11 year old cohorts were divided into pre- and postpubertal twin groups to more closely examine

the effect of puberty on the heritability of the characteristic traits and behaviors of anorexia (Klump, K.,

2001). The results demonstrated increased heritability in postpubertal relative to prepubertal twins who

were the same age provided strong evidence of potential pubertal activation of the heritability of eating

abnormalities that may be mediated by ovarian hormones. These findings are important for highlighting

not only developmental differences in genetic effects but also the potential role of ovarian steroids in the

heritability of the disorder (Klump, K., 2001).

In addition to the correlation between pubertal genetic activation, there has also been research involving

the association between Axis I psychological disorders and anorexia nervosa. One study in-particular

aimed to demonstrate the increased association between major depression and anorexia nervosa in

women (Wade, T., 2000). It was noted that in recent studies, lifetime major depression has been

reported in about 50% of the women with anorexia nervosa and the rates of major depression are

elevated in the first-degree relatives of women with anorexia nervosa. This co-morbidity has been

debated, and some authors contend that anorexia nervosa and major depression share a common

etiology, while others suggest that the liability for anorexia nervosa is distinct from that operating in the

transmission of affective disorders (Wade, T., 2000). A twin study was used in order to isolate the

phenotype of the subjects and to determine the effects of environment versus genetics. The interviewers

were blind to any information about the twins to avoid bias. To increase the statistical power of this study

of a disorder with such a low prevalence, a broad definition of anorexia nervosa was adopted. This

expansion of the definition of anorexia nervosa allowed the researchers to obtain useful estimates of the

genetic and environmental contributions to the liability of anorexia nervosa. The correlation was found to

be less than unity; therefore separate genes appear to contribute uniquely to the liability for anorexia

nervosa and major depression (Wade, T., 2000). This suggests that there is in fact a genetic component

in the development of anorexia, but the results of this study were claimed to be slightly ambiguous

(Wade, T., 2000). The causes of this ambiguity shall be discussed in the future.

Considering the abundance of results that lean toward a genetic component in the development of

anorexia nervosa, researchers have begun to directly examine the genetic influences through

association and linkage studies. Particularly, the relative influence of a specific gene or genetic marker

on the development of eating disorders was studied. This is accomplished by comparing the frequency of

the alleles from the parents to the children with anorexia. Linkage analysis is used to identify contributing

genetic loci by examining allele sharing among family members at several genetic markers across the

genome, examining all identified genetic markers in the genome (Klump, K., 2001).

An additional strategy used to examine genetic influences utilizes association studies. There is evidence

linking anorexia to monoamine functioning, which has led researchers to target serotonin and

dopamine-related genes in association analysis. Several studies have shown an increase in the -1438/A

allele of the 5-HT receptor gene in anorexic women when compared with controls. However, additional

studies have failed to show significant associations in subjects with anorexia as well as increased allele

frequencies of the dopamine D3 and D4 receptor genes in anorexic relatives to the control subjects

(Klump, K., 2001).

The pathology of anorexia has been attributed to the roles of weight control, feeding, and energy

expenditure, which has led researchers to examine genes related to these processes and their influence

on the development of the disorder. Several studies have been conducted examining the genetic risk

factors involved in the development of anorexia nervosa disclosing a relation between a polymorphism in

the promoter region of the 5HT2A gene (-1438G/A) and the presence of anorexia (Karwautz, R., 2001).

This mutation results in a trait-related disturbance of serotonin that could contribute to restricted eating,

behavior over-control, and obsessive exactness.

Brain serotonergic systems have been reported to regulate eating behaviors. The pharmacological

enhancement of serotonin (5HT) transmission generally leads to increased satiety. This is supported by

evidence of reduction in meal size, rate of eating, and body weight. The brain's hypothalamic 5HT

pathways are involved in post-ingestive satiety, and pre-meal administration of 5HT agonist drugs has

been proven to decrease food intake (Nishiguchi, N., 2001).

These pharmacological studies appear to support the involvement of functional alteration of

neurotransmission due to genetic polymorphisms of serotonergic receptors in the modulation of eating

and the development of eating disorders, particularly anorexia nervosa (Nishiguchi, N., 2001). In addition

to these studies, numerous researchers have succeeded in replicating the original finding that the

frequency of the -1438A/G polymorphism was significantly higher in patients with anorexia than in control

subjects. Evidence against these findings, however, has also been reported; thus, the association is

controversial (Nishiguchi, N., 2001).

In addition to the investigations involving serotonergic receptors, researchers have also been exploring

the possibility of involvement of dopamine receptors in anorexia nervosa. Dopamine is suspected to be

involved in the physiology of the disorder, amenorrhea, and the anticipation of heeding in humans. It has

also been implicated in the clinical symptoms of hyperactivity, distortion of body image, and the reward

and reinforcement processes (7).

Reinforcement is considered to be an addictive feature that could constitute a core symptom of anorexia

nervosa, exemplified in the characteristic lack of control involved in the disorder. The dopamine receptor

(D3) gene is expressed in restricted limbic areas such as the nucleus accumbens and the island of

Calleja. This suggests that this dopamine receptor could be more specifically involved in the

pathogenesis of anorexia nervosa. The mesolimbic mesocortical dopaminergic circuits innervate the

ventral striatum, notably the nucleus accumbens, which is one of the essential substrates for reward and

reinforcement behavior (Bruins-Slot, L., 1998). Although the research leans toward involvement of the

D3 receptor in the development of anorexia, no significant difference was found between allellic

distribution of this polymorphism in anorexia nervosa and a control group. Two factors, small sample size

and the fact that the sample population was distinguished by the clinical specifications of anorexia

nervosa limit this conclusion (Bruins-Slot, L., 1998).

Additional studies suggest that several heritable characteristics are commonly co-morbid with anorexia

and may share genetic transmission with the disorder (Klump, K., 2001). These disorders include anxiety

disorder or traits, body weight, and possibly major depression. Anorexics also tend to exhibit high levels

of harm avoidance, stress reactivity, and negative emotionality. It has been speculated that phenotypic

similarities between these traits and the rigidly preserving, obsessional, and anxiety-reducing character

of the anorexic's dietary restraint may be based on shared genetic and environmental factors (Kaye, W.,

2000). The moderately heritable characteristics of these conditions suggest that etiologic relationships

may be genetic (Klump, K., 2001). This is because genetic rather than environmental influences seem to

underlie phenotypic and familial relationships. But the results also indicate the presence of other genetic

influences on eating abnormalities that are independent of genes influencing personality characteristics

(Klump, K., 2001).

One study inparticular researched the prevalence anorexia nervosa in a controlled family study.

Their goal was to uncover the relationship between anorexia and genetics as well as its

relationship with the personality traits described above. They found that a higher lifetime

prevalence of the disorder in first-degree relatives of probands than in first-degree relatives of

psychiatric and normal controls (Kaye, W.,2000). They also uncovered a higher prevalence of

the obsessional personality traits, suggesting that obsessional traits may manifest the effects of

a genotype that increases susceptibility to anorexia (Kaye, W.,2000).

A number of other family studies have provided a necessary step in determining whether the

disorder is genetic by establishing whether it clusters among biologically related individuals. In

general, these studies have found an increased rate of eating disorders in relatives compared to

control relatives. The findings from the largest and most reliable studies suggest a 7-12-fold

increase in the prevalence of anorexia in relatives of eating-disordered probands (Klump, K.,

2001). However, given that first-degree relatives share genes and environments, these studies

are unable to differentiate genetic versus environmental causes for familial clusters. The

researchers have turned to twin studies to disentangle genetic and environmental effects

(Karwautz, R., 2001).

Reviews of twins with anorexia have consistently found an increased concordance rate for

eating disorders in monozygotic twins when conpared to dizygotic (Bruins-Slot, L., 1998). The

vulnerability component of anorexia nervosa that can be attributed to genetic influences, has

been estimated around 76% using evidence from these studies. They are able to differentiate

genetic from environmental effects by comparing similarity for a trait disorder between identical

and fraternal twins. The heritability estimates are similar to those found in studies of

schizophrenia and bipolar disorder, suggesting that anorexia may be as genetically influenced as

disorders traditionally viewed as biological (Klump, K., 2001). Although this information seems

promising, the findings of twin studies are inconsistent and difficult to interpret. The estimates for

the heritability of liability to anorexia nervosa is be 0% to 70%. Methodological reasons for this

variability include issues of, definition of phenotype, diagnostic reliability, violation of the equal

environments assumption, and small sample sizes (Klump, K., 2001).

Together the results suggest significant genetic and non-shared environmental influence on

anorexic pathology and that findings from patient-based samples are generalizable to individuals

in the general population, despite the low prevalence of this disorder in the population (Klump, K.,

2001). This disorder is complex and probably results from an interaction of genetic and

environmental factors, and an aetiological study should include both parameters (Karwautz, R.,

2001). The best design would be a prospective study but a sample size of 20,000-10,000 would

be needed to obtain 100 cases of the disorder. Alternative strategies would be to sample high

risk groups, but such approaches would require the preliminary identification of appropriate

measure and risk factors from retrospective analysis (Karwautz, R., 2001).


Bruins-Slot, L., Gorwood, P., et. al. "Lack of Association between Anorexia Nervosa and D3

Dopamine Receptor Gene." Society of Biological Psychology, 1998.

Nishiguchi, N., Matsushita, S., et. al. "Association between 5HT2A Recpetor Gene Promoter

Region Polymorphosm and Eating Disorders in Japanese Patients." Society of Biological

Pyschiatry, 2001.

Wade, T., Bulik, C., et. al. "Anorexia Nervosa and Major Depression: Shared Genetic and

Environmental Risk Factors." The American Journal of Psychiatry, 2000.

Klump, K., Miller, K, et. al. "Genetic and Environmental Influences on Anorexia Nervosa

Syndromes in a Population-Based Twin Sample." Psychological Medicine, 2001.

Karwautz, A., Rabe-Hesketh, S., et. al. "Individual-Specific Risk Factors for Anorexia Nervosa: A

Pilot Study Using a Discordant Sister-Pair Design." Psychological Medicine, 2001.

Klump, K., Kaye, W., et. al. "The Evolving Genetic Foundations of Eating Disorders." Psychiatric

Clinics of North America, 2001.

Kaye, W., Lilenfeld, L., et. al. "A Search for Susceptibility Loci for Anorexia Nervosa: Methods

and Sample Design." Society of Biological Psychiatry, 2000.


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