Breakthroughs in the Genetics of Anorexia Nervosa

In 1998 when Kartini Clinic was founded to serve children with “all conditions of disordered eating,” those with anorexia nervosa (AN) represented the majority of our young patients. At the time, I was nearly alone in my belief that AN was a biologically based disorder and probably highly heritable (i.e. “runs in families”). Even those colleagues who later came to agree with this point of view (Bryan Lask!) were, in those days, quite skeptical—not to say hostile—to this “reductionist” conceptualization of a condition widely regarded as caused by “enmeshed, dysfunctional mothering,” “male repression of the female body,” “maturational conflicts,” and by a host of other psychoanalytic and psychodynamic explanations. I have always found it funny to hear biological explanations characterized as “reductionist,” since nothing could be more complex!

From the first days of Kartini Clinic we “trawled” for associations in the only clinical way open to us as a fledgling treatment program: we took detailed family histories at the time of initial assessment. I insisted that we ask about other members of the extended family, and about “physical” illnesses as well as psychiatric illnesses. People were puzzled as to why we wanted to know about their family history of diabetes, autoimmune disorders, insomnia and cancer as well as neurotic traits and mental (aka brain) illness.

Now, in 2017, an important paper has finally appeared as the result of international efforts to define the genetic underpinnings of AN hinted at by earlier twin studies. Any scientific endeavor as important and difficult as the one led by Cindy Bulik and reported for the first time in the American Journal of Psychiatry takes years. We (Janiece Desocio and Julie O’Toole) are proud to be part of the Eating Disorders Working Group of the Psychiatric Genomics Consortium and collaborators on this paper. Kartini Clinic families contributed their genetic samples to this watershed study.

Here are some excerpts from the press release: “The study, which is the most powerful genetic study of anorexia nervosa conducted to date, included genome-wide analysis of DNA from 3,495 individuals with anorexia nervosa and 10,982 unaffected individuals. If particular genetic variations are significantly more frequent in people with a disorder compared to unaffected people, the variations are said to be “associated” with the disorder. Associated genetic variations can serve as powerful pointers to regions of the human genome where disorder-causing problems reside, according to the National Human Genome Research Institute.

“‘We identified one genome-wide significant locus for anorexia nervosa on chromosome 12, in a region previously shown to be associated with type 1 diabetes and autoimmune disorders,’ said lead investigator, Cynthia Bulik, PhD, FAED. […] ‘We also calculated genetic correlations – the extent to which various traits and disorders are caused by the same genes,’ said Bulik. ‘Anorexia nervosa was significantly genetically correlated with neuroticism and schizophrenia, supporting the idea that anorexia is indeed a psychiatric illness […] But, unexpectedly, we also found strong genetic correlations with various metabolic features including body composition (BMI) and insulin-glucose metabolism. This finding encourages us to look more deeply at how metabolic factors increase the risk for anorexia nervosa.’”

An important disclaimer: correlation is not causation! In other words, just because things occur together doesn’t necessarily mean one causes the other. Mistaking correlation for causation is one of the most important and deceptive thought errors made, even by scientists. Another important disclaimer: complex conditions like those studied here are not caused by a single aberrant gene, but rather are the result of multiple small contributions made by many different  SNP’s (single nucleotide polymorphism)

This paper is a highly technical read, but here is what jumped out at me: the (negative) association between obesity and anorexia nervosa does not mean that if you are obese you cannot have AN, or that one causes (or prevents) the other, but that both have metabolic underpinnings and consequences. Bulik says:  “Just as obesity is increasingly considered to be both a metabolic/endocrine and psychiatric disorder, approaching anorexia nervosa as both a psychiatric and metabolic condition could ignite interest in developing or repositioning pharmacological agents for its treatment.”

As tough as it was to be swimming upstream in the 90’s and early 2000’s in the belief that anorexia nervosa is a biologically based illness, in 2017 Kartini Clinic finds itself having to plead for a different understanding of obesity.  Obesity is not caused by gluttony, sloth and a stubborn refusal to act like a skinny person; it’s a metabolic disorder.

As Bulik says, there is a shared biology (yes, shared) between the extremes of weight dysregulation: “These observations extend our understanding that the same genetic factors that influence normal variation in BMI, body shape, and body composition may also influence extreme dysregulation of these weight-related features in anorexia nervosa.”

Readers of my blog know that at Kartini Clinic we have been exploring the metabolic consequences of recovery from anorexia nervosa, including low leptin, low glucose, low insulin, and post-prandial hypoglycemia. One thing we know from our clinical experience and laboratory testing is that those in recovery from AN resemble those with the metabolic condition known as obesity—with one big difference: people suffering from one condition are met with compassion and even admiration, and those suffering from the other with derision and scorn.  It is my hope that the work we are doing in the metabolic consequences of re-feeding, now echoed in this important study, will bring the clarity and understanding that only science can bring to an issue that affects millions.