Skip to main content
Full access
Editorials
Published Online: 1 September 2017

New Genetic Discoveries in Anorexia Nervosa: Implications for the Field

Anorexia nervosa is a chronic and often life-threatening illness with stable prevalence across cultures and populations (1). Once described primarily as a disease with psychological underpinnings, it is now recognized as a biologically based, heritable syndrome. As with other psychiatric disorders (2), it is likely that many genetic variants, each of very small effect size, contribute to risk for anorexia nervosa. Unlike in several other major psychiatric disorders, progress in the identification of genetic risk factors associated with anorexia nervosa has been slow, and there remains a notable absence of implicated genes with known influence over the brain.
In this issue, Duncan et al. (3) describe a genome-wide association study (GWAS) of anorexia nervosa and related metabolic phenotypes. The authors combined several case-control data sets for enhanced power to detect effects of common variation on the illness and investigated correlations with other psychiatric, educational, and metabolic phenotypes. The GWAS approaches and genetic analyses follow the current standard rubric, and the results are consistent with what has been reported in other psychiatric disorders at a similar stage of discovery. The results indicate one GWAS significant signal that has previously been linked with type 1 diabetes and autoimmune disorders. Furthermore, the authors report the single-nucleotide polymorphism–based heritability estimates to be significant, suggesting that there is a substantial contribution of common genetic variation to anorexia nervosa. There are a number of genes in the top region of association; the closest of these genes is ERBB3, which binds neuregulin, a gene also implicated in schizophrenia (4). This finding is consistent with positive genetic correlations noted in the article between anorexia nervosa and schizophrenia. These results are highly consistent with previous reports in the broader psychiatric genetics literature suggesting significant overlap among genetic risk factors for many neuropsychiatric diseases. Indeed, one of the most interesting aspects of this study, and potentially the most informative, is the genetic correlations with multiple other phenotypes of interest that point toward important pathophysiologically relevant overlap among metabolic markers, cognitive/personality traits, and disease. These associations with “intermediate phenotypes” help us understand how a single risk allele might act to influence disease susceptibility in a broad, transdiagnostic manner.
The genetic correlations that are reported between anorexia nervosa and metabolic markers are critically important in emphasizing that this illness is one of both mind and body. However, there are some limitations of the study that prevent the drawing of firm conclusions. The authors emphasize the question of the validity of the links to body mass index, insulin resistance (HOMA-IR), and high-density lipid levels, as these values can all be confounders, depending on the nature of the disease. To further clarify these relationships, significant follow-up would be required, ideally in a study with a group of negative control subjects who experienced significant weight loss but did not have anorexia nervosa. Such a control group would be helpful in delineating what is common among psychiatric and metabolic symptoms and what might be specific to only one of these phenotypes.
While the reported genetic correlation between anorexia nervosa and educational attainment is consistent with past reports, it has previously been described as being related to other factors, such as higher socioeconomic status in families of individuals with anorexia nervosa (5). These results add to the evidence that these relationships are likely to be influenced by both genes and environment. They also point toward the complex nature of the phenotypes being studied; while educational attainment is thought to be a good proxy for cognitive capacity or intelligence, it almost certainly also reflects other traits, such as neuroticism (6).
Where do we go from here? The sample size for anorexia nervosa cases is still on the small side for a GWAS, and the authors mention that all available genotyped samples in the world are included here. This raises several questions regarding the impact of the results, which are likely to remain the motivating results in the field for years to come. Based on patterns seen in other major psychiatric illnesses (e.g., schizophrenia and bipolar disorder), how likely is it that the strongest statistical signal (at p<10−9) will remain significant with larger samples? Would we expect to find the same number of common risk variants as is seen in other disorders if sample size continued to increase? If so, how might the field move forward from here? As is often the case, in an effort to increase sample size and power, there is a need to include somewhat heterogeneous cases (e.g., combining restricting type and binge-purging type anorexia nervosa), where there may be different underlying genetic or composite risk factors. This is a minor limitation and one that could be followed up in secondary analyses. Finally, one of the important aspects of the illness that is not discussed in this study is the notable sex imbalance in anorexia nervosa (a 10:1 female-to-male ratio). This will be important to investigate in future work or in subsequent analyses of this data set—for example, utilizing sex-adjusted or sex-specific analyses.
Anorexia nervosa is a difficult-to-treat illness, and there remains a desperate need to develop unique approaches to treat patients with chronic cases of the disorder. The results reported by Duncan et al. support an important new direction for research in this area and will motivate searches into metabolic and immunological factors of the disorder.

References

1.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC, American Psychiatric Association, 2013
2.
Cross-Disorder Group of the Psychiatric Genomics Consortium: Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 2013; 381:1371–1379
3.
Duncan L, Yilmaz Z, Gaspar H, et al: Significant locus and metabolic genetic correlations revealed in genome-wide association study of anorexia nervosa. Am J Psychiatry 2017; 174:850–858
4.
Mostaid MS, Lloyd D, Liberg B, et al: Neuregulin-1 and schizophrenia in the genome-wide association study era. Neurosci Biobehav Rev 2016; 68:387–409
5.
Goodman A, Heshmati A, Koupil I: Family history of education predicts eating disorders across multiple generations among 2 million Swedish males and females. PLoS One 2014; 9:e106475
6.
Trampush JW, Yang ML, Yu J, et al: GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium. Mol Psychiatry 2017; 22:336–345

Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 821 - 822
PubMed: 28859512

History

Accepted: June 2017
Published online: 1 September 2017
Published in print: September 01, 2017

Keywords

  1. Genetics
  2. Eating Disorders

Authors

Details

Pamela B. Mahon, Ph.D.
From the Department of Psychiatry, Brigham and Women’s Hospital, and the Department of Psychiatry, Harvard Medical School, Boston; and the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York.
Thomas B. Hildebrandt, Psy.D.
From the Department of Psychiatry, Brigham and Women’s Hospital, and the Department of Psychiatry, Harvard Medical School, Boston; and the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York.
Katherine E. Burdick, Ph.D. [email protected]
From the Department of Psychiatry, Brigham and Women’s Hospital, and the Department of Psychiatry, Harvard Medical School, Boston; and the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York.

Notes

Address correspondence to Dr. Burdick ([email protected]).

Funding Information

Dr. Mahon reports no financial relationships with commercial interests. Dr. Hildebrandt has equity in Noom, Inc. Dr. Burdick has served on advisory boards for Otsuka, Takeda, Lundbeck, Sunovion, Sumitomo Dainippon Pharma, and Neuralstem. Dr. Freedman has reviewed this editorial and found no evidence of influence from these relationships.

Metrics & Citations

Metrics

Citations

Export Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format
Citation style
Style
Copy to clipboard

View Options

View options

PDF/EPUB

View PDF/EPUB

Login options

Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.

Personal login Institutional Login Open Athens login
Purchase Options

Purchase this article to access the full text.

PPV Articles - American Journal of Psychiatry

PPV Articles - American Journal of Psychiatry

Not a subscriber?

Subscribe Now / Learn More

PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.

Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).

Media

Figures

Other

Tables

Share

Share

Share article link

Share