The role of genetics
Family and twin studies
Patients with eating disorders have consistently reported the presence of either frank eating disorders or suggestive traits in family members. Most commonly, the clinician hears of a relative who ate exceedingly sparingly or had quirky eating behaviours. Although perhaps unnamed and undetected, such behaviours often suggest a threshold or subthreshold eating disorder that may be discerned by further inquiry. Formal family studies of both anorexia nervosa and bulimia nervosa have shown that these disorders are substantially familial. Relatives of patients with eating disorders have approximately a 10-fold greater lifetime risk of such disorders than relatives of unaffected people.4,5,12,13,14
Moreover, mirroring the common clinical observation of diagnostic crossover,15
family studies indicate that these disorders do not “breed true”: relatives of people with anorexia nervosa may themselves have a more bulimic clinical presentation and vice versa.4,5
Further insight into familial transmission has been provided by twin studies, which, unlike family studies, allow the researcher to parse out sources of familial aggregation, at least to some extent. Variance in susceptibility to eating disorders can be partitioned into additive genetic, shared environmental and unique environmental factors. Eating disorders are complex traits, and additive genetic effects are the cumulative effects of many genes, each of which has a small to moderate effect. Shared environmental factors contribute to the similarity of twins and reflect environmental influences to which both members of a twin pair are exposed. Finally, unique environmental factors, which include error of measurement, refer to environmental forces to which only one member of a twin pair is exposed. With this information, heritability can then be calculated; however, any heritability estimate is a product of trait prevalence, monozygotic twin concordance and dizygotic twin concordance and is specific to a given population at a particular point in time. As such, there is no single definitive heritability estimate for anorexia nervosa. The influence of changing prevalence on heritability was nicely illustrated by Kendler et al,16
who compared the heritability of tobacco use in Sweden between 2 historical cohorts — one in which smoking was relatively rare among women and the other in which smoking had become more prevalent throughout society. The heritability of tobacco use in men in these 2 cohorts remained similar over time (about 63%) (as did prevalence, since there were no prohibitions against men smoking). In contrast, the heritability of tobacco use in women jumped from near 0% to 63%. These results illustrate the importance of a deep understanding of the factors that influence any heritability estimate and the context in which it is measured.
Several twin studies of eating disorders and related traits have now been conducted in many countries around the world, including the United States, the United Kingdom, Australia, Norway, Sweden, Finland and Denmark. These studies have consistently revealed moderate contributions of the additive effects of genes.6,7,9,17,18,19
Heritability estimates have ranged from 33% to 84% for anorexia nervosa,8,19,20,21
between 28% and 83% for bulimia nervosa (reviewed by Bulik and Tozzi11
) and 41% (confidence interval 31%–50%) for binge-eating in the absence of compensatory behaviours (a proxy for binge-eating disorder),22
with the remaining variance (in each disorder) attributable to individual specific environmental factors and negligible impact of shared environmental factors. Most of these estimates have been fairly imprecise as reflected in the broad confidence intervals. Nonetheless, consistent replication across samples and across countries, despite different assessment and diagnostic strategies, supports the observation that there is indeed some critical genetic component influencing risk for these disorders.
Moreover, certain assumptions, such as the equal environment assumption, must be met in twin studies to avoid bias in the derived estimates. The equal environment assumption posits that monozygotic twins are not treated more similarly than dizygotic twins on factors of causative relevance to the disorder. For example, although monozygotic twins might be dressed alike more frequently than dizygotic twins, dressing alike is unlikely to be a factor of major causative relevance to eating disorders. To date, no such gross violations have been observed, which lends further credence to the observed results.9,23,24
It is critical that all of the twin studies of eating disorders have been conducted in primarily European populations. Little is known about the heritability of these disorders and traits in other cultures and ethnic groups.
Association and linkage studies
With a plethora of studies now emerging, several reviews of the molecular genetics of eating disorders have been published.10,11,25
Both association studies, which compare people displaying a trait of interest with controls who do not display the trait and then determine the genotypes of all subjects for a candidate gene or genes hypothesized to be of relevance to the phenotype, and linkage studies, which require a large sample of multiplex pedigrees or extreme sibling pairs,26
have been conducted for eating disorders.
The corpus of association studies reveals occasionally significant but often unreplicated findings. Because of the role of serotonin in feeding and mood, genes in the serotonergic system have received particular attention. Associations have been observed with the serotonin receptors 2A27,28,29,30,31
as well as the serotonin transporter gene,34,35
although replication of results has not been universal.36,37,38,39,40,41,42,43
Steiger et al44
examined factors associated with the promoter region of the serotonin transporter gene (5-HTTPLR
) in women with “binge–purge syndromes” (which included bulimia nervosa, eating disorder not otherwise specified and anorexia nervosa bingeing-purging subtype). Although the S
allele was not associated with eating disorder symptoms or related traits, it was
associated with borderline personality disorder and impulsive traits. Moreover, the presence of the S
allele was associated with a significantly lower density of paroxetine binding sites, which suggests that these patients might not respond as well to traditional selective serotonin reuptake inhibitors. Steiger et al hypothesized that differences in paroxetine binding might be due to an interaction of environmental and genetic factors, given that chronic food restriction in animals is associated with serotonin dysregulation. That study highlighted the importance of measuring specific traits associated with eating disorders and the potential richness of exploring gene–environment interactions that may affect therapeutic response.
Other systems of interest in the development of eating disorders include norepinephrine45,46
genes. Although these studies have not been universally replicated, patterns are emerging in the literature on the genetics of eating disorders. Ultimately, these genetic investigations could lead to further elucidation of the neurobiologic pathways implicated in eating disorders and might reveal rational drug targets.
Linkage studies for both anorexia nervosa and bulimia nervosa48,49,50,51,52
have underscored the importance of looking beyond the diagnoses of the Diagnostic and Statistical Manual of Mental Disorders
, fourth edition,53
that have been identified in genetic studies and seeking reliable endophenotypic traits that might bring us closer to the core neuropathology of these disorders. Focusing on the most homogenous presentation of anorexia nervosa — the classic restricting subtype of anorexia nervosa in the absence of binge-eating behaviour — yielded evidence for a susceptibility locus on chromosome 1.50
Further analyses of this data set led to the incorporation of behavioural covariates into linkage analyses. Devlin et al49
selected and incorporated core behavioural covariates (drive for thinness and obsessionality) into the linkage analysis. The inclusion of these covariates revealed several regions of interest on chromosomes 1, 2 and 13. This team has also explored the regions under the linkage peaks for association.54
Both serotonin 1D (HTR1D
) and delta opioid (OPRD1
) receptor genes exhibited significant association with anorexia nervosa. The only published linkage study of bulimia nervosa51
reported significant linkage on chromosome arm 10p for a broad sample of families with this condition.
Although genetic research has catapulted the field into a new era, genes paint only part of the picture. The identification of genes that influence risk for eating disorders does not mean that attempts to reduce noxious environmental exposures, such as unrealistic expectations about physical appearance and slenderness, should be eased. Yet how can genetic research help in identifying which individuals might be differentially vulnerable to these environmental insults?
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