Genetic Factors of Eating Disorders

Even though genetic studies may not currently impact treatment for individual patients, there is still value in understanding the genetic components of eating disorders. Knowing what genes predispose individuals for eating disorders may lead to better treatment options in the future.  

Are Eating Disorders Genetic?

Research is still emerging on the role genetics play in the risk of developing an eating disorder, but current studies suggest that a significant portion of the risk may be genetic.^1,2 Most studies focus on anorexia nervosa and bulimia nervosa. Studies on binge eating disorder (BED) are rare.

Eating disorders are known as “perfect storm” illnesses, where development is attributed to a mix of different factors, including:

• Genetic predisposition
• Sociocultural factors
• Psychiatric comorbidities
• Personality traits

Understanding the genetic basis for eating disorders offers one avenue of understanding why eating disorders develop and may lead to better treatment options.  

Eating Disorder Diagnoses

Anorexia Nervosa

Anorexia nervosa is the most frequently studied eating disorder, including genetic studies. It is categorized by:³

• Restriction of energy intake relative to requirements, leading to significantly low body weight in the context of age, sex, developmental trajectory and physical health
• Intense fear of gaining weight or becoming fat or persistent behavior that interferes with weight gain
• Disturbed by one's body weight or shape, self-worth influenced by body weight or shape, or persistent lack of recognition of the seriousness of low body weight

Bulimia Nervosa

Bulimia nervosa is another eating disorder that’s been genetically studied. It is marked by recurrent episodes of binge eating followed by inappropriate compensatory behaviors.³ It is usually linked to a strong fear of gaining weight and a distorted body image, despite often maintaining a normal weight. 

Binge Eating Disorder

Binge eating disorder is less studied than anorexia nervosa and bulimia nervosa. It is an eating disorder consisting of episodes of binge eating – consuming large quantities of food in a brief period – without the use of a compensatory behavior.³

Family History & Genes

Family studies

Family studies measure how much genetic factors influence differences among individuals. They indicate a familial risk for eating disorders but cannot exclude environmental influences.

Relatives of someone with anorexia nervosa or bulimia nervosa have been shown to have a higher risk of developing either disorder.³ Larger studies suggest up to a 12-fold increase in likelihood for anorexia nervosa.^1,2 Relatives of probands with bulimia nervosa are also more likely to be diagnosed with BN, with nine times greater risk than controls.⁵

Binge eating disorder is also more likely to occur in family members of probands, but the risk is lower than those with anorexia nervosa and bulimia nervosa.⁶

Twin studies

Twin studies are studies that compare identical and fraternal sets of twins to determine liability (an individual's innate tendency to develop a disease). Unlike family studies, where genetics are not When the environment is shared and individuals are identical, twin studies offer deeper insights — identical twins share the same genes and environment while fraternal twins share the same environment and only 50% of the same genetics, allowing researchers to separate genetic and environmental risk factors better.

Twin studies estimate that:⁴

• Up to 74% of variability of anorexia nervosa is genetic
• Up to 62% of variability of bulimia nervosa is genetic
• Up to 45% of variability of BED is genetic

It’s important to note that these percentages do not indicate what proportion of a trait is determined by genetic factors or the likelihood of developing a trait, but rather what percentage of the variability in a trait in a population is due to genetic differences.

Adoption studies

Adoption studies are rare, with only one documented study on eating disorder pathology. These studies are valuable because biological relatives only share genetics with the proband, whereas adoptive relatives only share environment.

In this single study, genetic influences were a significant contributor to the development of disordered eating, while shared environmental factors did not significantly contribute.⁷

Molecular Genetics

Molecular genetic studies, such as linkage studies, genome-wide association (GWA) studies, candidate gene studies and genome-sequencing have all been used to analyze the structure and function of genes and their role in the development of eating disorders.

Eating disorder linkage studies

Linkage studies are used in gene discovery, utilizing genetic markers to pinpoint chromosomal regions that may contain genes contributing to eating disorders. These studies have identified several regions of interest on chromosomes 1, 2, 4, and 13, although they often do not pinpoint specific vulnerability genes.⁴

Genome-wide association studies

A genome-wide association study (GWAS) is a method that quickly scans markers across the genomes of many individuals to find genetic variations linked to specific diseases. Once new genetic associations are found, researchers can use this information to improve strategies for detecting, treating and preventing the disease.

Two loci associated with anorexia nervosa (physical sites within a genome) have been identified by GWAS. One study found a significant association, nearing genome-wide significance, between a variant in the Early B-Cell Factor 1 (EBF1) gene and it may influence circulating leptin levels, consistent with the very low leptin levels observed in human patients with AN.⁸ Another study identified a region linked to autoimmune disorders.⁹

Eating Disorder Candidate Gene Association Studies

Candidate gene association studies examine the genetic variation linked to disease within a small number of pre-selected genes. Many candidate gene studies on common variants related to eating disorders have been published, but none are conclusive.

Regardless of the type of eating disorder, most research has focused on homeostatic control and reward system pathways because they are believed to share pathways with eating disorders. This is based on the idea that healthy eating behavior results from a balance between homeostatic controls and reward processes.

The main pathways explored in candidate gene studies of eating disorders are as follows:⁴

• Homeostatic pathways
  • Leptin melanocortin pathway genes (i.e. LEP, LEPR, POMC, AGRP, MC4R, BDNF genes, as well as GHRL, FTO genes)
• Reward-related pathways including
  • Central neurotransmission of serotonin (i.e., HTR1D, HTR2A, HTR2C, SLC6A4 genes)
  • Dopamine (i.e., DRD2, DRD4, ANKK1 genes)
  • Noradrenaline (COMT gene)
  • Opioid (OPRD1, OPRM1 genes)
  • Cannabinoid endogenous system (CNR1 gene)

Dysregulation of homeostatic and reward processes is observed in EDs, but it is currently unknown if alterations to these pathways are a cause or an effect.

Eating Disorder Genome Sequencing

Whole genome sequencing is the process of determining nearly the entire DNA sequence of an organism's genome at once. 

Whole-exome and whole-genome sequencing of two multigenerational pedigrees affected by multiple eating disorders identified the estrogen-related receptor-α (ESRRA) and the histone deacetylase 4 (HDAC4) genes as promising candidates for further study.¹⁰

Epigenetics: Eating Disorders Changing DNA

Epigenetics is the study of how behavior and environmental factors can cause changes that influence how genes function.

The most studied mechanism of epigenetics is DNA methylation, including both hyper- and hypomethylation, which affects the ability of DNA to replicate.⁴ Nutrition can influence methylation, but there is currently no evidence of an epigenetic pattern with anorexia nervosa.

The Future of Eating Disorder Treatment

The future of eating disorder research focuses on combining large-scale genomic data with epigenetic, neurobiological and environmental information to better understand risk factors.

Advances in GWAS, sequencing and polygenic risk scores could allow for earlier detection of high-risk individuals and more personalized prevention and treatment approaches.

Long term, this research aims to uncover biological pathways underlying eating disorders to develop precise interventions.

References

1. Strober, M., Freeman, R., Lampert, C., Diamond, J., & Kaye, W. H. (2000). Controlled family study of anorexia nervosa and bulimia nervosa: evidence of shared liability and transmission of partial syndromes. American Journal of Psychiatry, 157(3), 393–401. https://doi.org/10.1176/appi.ajp.157.3.393
2. Lilenfeld, L., Kaye, W. H., Greeno, C. G., Merikangas, K. R., Plotnicov, K., Pollice, C., Rao, R. G., Strober, M., Bulik, C. M., & Nagy, L. M. (1998a). A controlled family study of anorexia nervosa and bulimia nervosa. Archives of General Psychiatry, 55(7), 603. https://doi.org/10.1001/archpsyc.55.7.603
3. American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Washington, DC: APA.
4. Bulik, C., Yilmaz, Z., & HArdaway, A. (2015). Genetics and epigenetics of eating disorders. Advances in Genomics and Genetics, 131. http4s://doi.org/10.2147/agg.s55776
5. Psychiatric disorders in the first-degree relatives of probands with bulimia nervosa. (1989). American Journal of Psychiatry, 146(11), 1468–1471. https://doi.org/10.1176/ajp.146.11.1468
6. Hudson, J. I., Lalonde, J., Berry, J. M., Pindyck, L. J., Bulik, C. M., Crow, S. J., McElroy, S. L., Laird, N. M., Tsuang, M. T., Walsh, B. T., Rosenthal, N., & Pope, H. G. (2006). Binge-Eating disorder as a distinct familial phenotype in obese individuals. Archives of General Psychiatry, 63(3), 313. https://doi.org/10.1001/archpsyc.63.3.313
7. Klump, K. L., Suisman, J. L., Burt, S. A., McGue, M., & Iacono, W. G. (2009). Genetic and environmental influences on disordered eating: An adoption study. Journal of Abnormal Psychology (1965), 118(4), 797–805. https://doi.org/10.1037/a0017204
8. Li, D., Chang, X., Connolly, J. J., Tian, L., Liu, Y., Bhoj, E. J., Robinson, N., Abrams, D., Li, Y. R., Bradfield, J. P., Kim, C. E., Li, J., Wang, F., Snyder, J., Lemma, M., Hou, C., Wei, Z., Guo, Y., Qiu, H., . . . Hakonarson, H. (2017). A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling. Scientific Reports, 7(1). https://doi.org/10.1038/s41598-017-01674-8
9. Duncan, L., Yilmaz, Z., Gaspar, H., Walters, R., Goldstein, J., Anttila, V., Bulik-Sullivan, B., Ripke, S., Thornton, L., Hinney, A., Daly, M., Sullivan, P. F., Zeggini, E., Breen, G., Bulik, C. M., Duncan, L., Yilmaz, Z., Gaspar, H., Walters, R., . . . Bulik, C. M. (2017). Significant locus and metabolic genetic correlations revealed in Genome-Wide Association study of anorexia nervosa. American Journal of Psychiatry, 174(9), 850–858. https://doi.org/10.1176/appi.ajp.2017.16121402
10. Cui, H., Moore, J., Ashimi, S. S., Mason, B. L., Drawbridge, J. N., Han, S., Hing, B., Matthews, A., McAdams, C. J., Darbro, B. W., Pieper, A. A., Waller, D. A., Xing, C., & Lutter, M. (2013). Eating disorder predisposition is associated with ESRRA and HDAC4 mutations. Journal of Clinical Investigation, 123(11), 4706–4713. https://doi.org/10.1172/jci71400