Two Mutations Are Tied to Risk of Developing an Eating Disorder

Whole-genome sequencing
identified the mutations.

Reprinted from Eating Disorders Review
November/December Volume 24, Number 6
©2013 Gürze Books

Greater understanding of genetics is providing breakthroughs and answers to some of Medicine’s most perplexing problems. Anorexia nervosa (AN) and bulimia nervosa (BN) are believed to result from a complex interaction between genetic predisposition and environmental risk factors. A multi-center research team led by Huxing Cui, MD, at the University of Iowa Carver College of Medicine, Iowa City, and clinicians at the University of Texas Southwestern Medical Center recently identified two mutations associated with the risk of developing eating disorders (J Clin Invest 2013; doi:10.1172/JC17400).

Although such mutations are rare, and occur in fewer than 1% of the population, about 85 to 90% of the family members who carried one of these mutations developed either AN or BN. This compares to a prevalence of 1% to 4% in the general population, according to Dr. Michael Lutter, assistant professor of psychiatry at the University Of Iowa College Of Medicine.

Dr. Cui and colleagues used whole-genome sequencing after linkage mapping or whole-exome sequencing to study two families with multiple members affected by eating disorders. Whole-genome sequencing determines the complete DNA sequence of an organism’s genome at a single time, including all chromosomal DNA. In any biological sample containing a full copy of the DNA—even a very small amount of DNA or ancient DNA—can provide the genetic material necessary for full genome sequencing. In the first family (AN1), analysis of 20 members across three generations identified a rare missense mutation in the estrogen-related receptor-alpha (ESRRA). (A missense mutation is a genetic change that results in the substitution of one amino acid in protein for another, and may lead to a disease or disorder.). In the second family (AN2), analysis of 8 members across four generations identified a missense mutation in the histone deacetylase 4 (HDAC4) gene that segregated with illness. Mutations that result in decreased ESRRA activity increased the risk of developing an eating disorder.

ESRRA is an orphan nuclear receptor with sequence homology to estrogen receptors, plays a role in energy balance and metabolism, and is up-regulated by exercise and caloric restriction. HDAC4 is a transcriptional repressor implicated in a number of actions relevant to eating disorders, including locomotor activity, body weight homeostasis, and neuronal plasticity, according to the authors. These genes seem to be turned on by caloric restriction and exercise, and enable the body to adapt to a low-calorie state.

The authors noted that in family studies such as these, the clinical and diagnostic picture is often complicated by environmental and psychological factors that encourage disordered patterns of eating, which further complicate the assignment of subjects to “affected” or “unaffected” categories. However, the large number of family members affected, young age of onset of illness, extremely low body weights, long term of illness and in one family, multiple affected male family members, pointed to a possible genetic cause. To avoid any mis-categorization of the participants, only family members with full diagnoses of AN or BN were included; those diagnosed with eating disorder not otherwise specified (EDNOS) were categorized as “subsyndromal.”

Differences between the families

Several interesting differences were noted between the two families. The AN-1 family had a high comorbidity of obsessive-compulsive disorder (OCD): 8 of 10 affected family members had a comorbid Axis I diagnosis of OCD. In contrast, the AN-2 family had significantly lower rates of comorbid anxiety disorders and OCD, but higher rates of BN. More clues may come from the families themselves. In the AN-1 family 2 males are affected with eating disorders, while in the AN-2 family, 2 male members appear to be unaffected carriers.

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