Metabolic Mystery Revealed

Anorexia nervosa is a devastating disorder – psychologically and physically damaging, tenacious in its grip on those diagnosed, and sometimes even fatal. It is usually diagnosed and treated by a psychiatrist – but now, new research asks: is the disorder exclusively a mental illness? A genome-wide association study (GWAS) conducted by researchers at the University of North Carolina School of Medicine has discovered strong correlations with psychiatric traits like neuroticism and schizophrenia – but, unexpectedly, also with metabolic features, such as insulin-glucose metabolism. Cynthia Bulik, Professor of Medical Epidemiology and Biostatistics at Karolinska Institutet and Founding Director of the UNC Center of Excellence for Eating Disorders, discusses her team’s discovery of a significant locus for anorexia nervosa on chromosome 12 (1).

What’s the importance of the newly discovered locus?

It’s the first significant locus discovered for anorexia nervosa – in an area that has been previously associated with type 1 diabetes and autoimmune illnesses. As we have seen in other psychiatric disorders, the discovery of the first significant locus tends to mark an inflection point in genomic discovery. We are actively increasing sample size (13,000 cases currently queued for genotyping).

Anorexia nervosa has always been an enigma. Especially puzzling is how these individuals can reach and maintain such low BMIs. Moreover, we have had no explanation for how or why, after therapeutic re-nourishment, their bodies rapidly rebound to the previous low BMIs. It makes me wonder whether what we are seeing is, in essence, the opposite of obesity. Individuals who are obese and diet down to a lower weight are known to regain that weight (and more) – a phenomenon that has been described as a “high set point.” It’s possible that what we see in anorexia nervosa is essentially the opposite – the body returning to a low set point. To date, we have primarily turned to psychological explanations for this repeated loss of weight. Now, our data suggest that we need to explore metabolic factors as well. That was the biggest eye-opener for us. We hadn’t anticipated that the associations with anorexia nervosa would be so strong.

Will this help diagnose or stratify patients with the disorder?

That’s our hope. We have been notoriously ineffective in treating anorexia nervosa, especially in adults. There are no medications that effectively treat the illness, nor any that target the underlying biology (because, until now, it has been poorly understood). Of course, we hope that genomic discovery will lead us in the direction of biologically or genetically informed therapeutic options.

In the future, using other genomic techniques, we may discover that some cases of anorexia nervosa are more strongly metabolic than others – or more strongly psychiatric. The ability to distinguish between different “subtypes” could potentially help guide our therapeutic approach.

First, though, we need a much more thorough understanding of the disorder’s genetics. The next step is to increase sample size and conduct additional analyses. We expect, based on GWAS for other disorders, that we will discover additional significant loci.

How did you bring together such a large collaboration?

The Psychiatric Genomics Consortium (med.unc.edu/pgc) was founded in 2007. It first focused on schizophrenia, major depressive disorder, autism, ADHD, and bipolar disorder. I watched their progress and decided that it was essential to develop an eating disorders working group. I could see that it was important to rapidly unite researchers and clinicians around the world in a quest to discover the genes that contribute to eating disorders.

What we’ve achieved so far is a brilliant example of what can be accomplished through global collaboration. It’s so clear that we are scientifically stronger as a team than we could ever be individually. I hope other laboratory medicine professionals take the same route – together, we can accomplish so much!