by Cynthia M. Bulik PhD

This is the fourth in a series of blog posts about recent results from the Anorexia Nervosa Genetics Initiative study published in Nature Genetics. Part 1 details our results, Part 2 the process, and Part 3 is an interview with Dr. Patrick Sullivan about the future of eating disorders genetics research.

Recently Dr. June Alexander asked me in an interview how I felt when we started ANGI and how I am feeling about the results today. I responded that six years ago, when we started ANGI, I was both daunted and determined. Some people doubted we could obtain blood samples from 13,000 individuals with anorexia nervosa, but to be honest I never doubted that we would. My certainty came from working in this field since 1982! Having worked with people with anorexia nervosa and their families on three continents and across 4 decades, I had a pretty solid sense of how desperate they were for answers and how unsatisfied they were with our current understanding of and treatment of this devastating illness. In addition, I also knew in my heart that the compassion I had seen in so many patients (often before they could recognize it in themselves) would drive their willingness to participate and give back in the hope that others would not have to ensure the suffering that they had. My intuition proved to be correct. I think in our next stages when we expand our sample size and open up recruitment to bulimia nervosa and binge-eating disorder things will go even better because we no longer need blood samples! Technology has advanced in the past six years such that a simple saliva sample will allow us to do the same analyses that we needed blood for in ANGI.

A new explanatory framework. Our results and our conclusion that anorexia nervosa may best be conceptualized as a metabo-psychiatric illness are meaningful to patients and families in that they provide a new explanatory framework for understanding the illness. From my earliest days in this field, the purely sociocultural explanations for anorexia nervosa just never rang true. Sure, dieting to achieve a thin ideal might start the process in some cases, but it sure didn’t explain why if we were all exposed to that thin ideal, why we didn’t all develop anorexia. Nor did it explain why individuals with anorexia nervosa lost weight far beyond any societal ideal that might show up on the cover of a glossy magazine. Something was missing. So often parents would describe these incredible transformations in their children that marked their descent into anorexia and their relief during recovery when they could see glimmers of their pre-illness child again. Patients described wanting to eat and wanting to be well, but not being able to push through an impenetrable barrier that would allow them to eat and gain weight. I guess you could say that my career has been a quest to find an explanation that actually fit and accurately accounted for the most perplexing aspects of anorexia nervosa.

Some of the most perplexing aspects are: How do people with this illness actually reach and maintain such low weights? Why is negative energy balance (expending more calories than one consumes) reinforcing for them? Why do their bodies drop weight so quickly even after medically-supervised renourishment? Why does physical activity seem to be more reinforcing than food? Why do they go through a hypermetabolic period during renourishment in which they burn through calories in ways that our equations simply cannot predict? So many unanswered questions. In retrospect, it is crystal clear that all speak directly to a metabolic component to the illness.

The importance of renourishment. Our results do not yet tell us the nature of the metabolic component, in fact, that is an important follow-on topic to be researched. But they do offer some important suggestions about treatment. For example, many of our interventions focus on the importance of restoring and maintaining a healthy weight as a cornerstone of recovery. Family-based treatment (FBT), specialist supportive clinical management (SSCM), cognitive-behavioral therapy-enhanced (CBT-E), and clinical guidelines all focus on the importance of weight restoration and normalization of eating. Yet for one reason or another, many treatments might stop short of these goals—partial weight restoration and partial normalization of eating. Although this is speculative, our results raise the question of whether these partial attempts may inevitably lead to treatment failure or relapse because they do not give the metabolism an opportunity to equilibrate or reset. If a patient is prematurely discharged from an inpatient renourishment program due to insurance coverage, chances are good that they will end up back on the unit at a low weight in the near future, ultimately costing more money and creating more distress for both patient and family.

Avoiding negative energy balance. Similarly, I have always warned patients and families to avoid negative energy balance even after long-term recovery. This recommendation was always just based on clinical observation. Too many times I had seen someone go through a stressful period when they skipped meals, or overseas travel disrupted their eating schedule leading to a full-blown relapse (even after years of recovery). Now, perhaps the explanation lies in our results. Maybe negative energy balance is the switch that engages whatever metabolic process it is that begins the descent into anorexia nervosa. If anything, I feel more confident in that recommendation now given our findings. Basically, anorexia nervosa becomes part of your health legacy. That does not mean that you cannot recover, but it does mean that you need to be vigilant. I draw an analogy to my own back injury. Three bones in my back were broken in 1978 when some drunken fans picked me up and passed me up in the stands at a Notre Dame football game…then dropped me. Those bones healed completely, but I have had to do back-strengthening exercises every day since and be mindful of positions or activities that could place me at risk for a back relapse. The thrill seeker in me would have loved to try bungy jumping, but the risk was too high. That event is part of my health legacy that I need to respect. Likewise, if you had anorexia nervosa, you need to be vigilant for and avoid negative energy balance, because the risk is just too high.

What about genetic risk? Another question that our work raises in people who have had anorexia nervosa is what this means for their next generation. The most important thing to remember is that genetics is not destiny! Anorexia nervosa is a classic complex trait, influenced by hundreds if not thousands of genes of small to moderate effect as well as environmental factors. In fact, you can look at your (and your offspring’s) risk as a combination of four factors: genetic risk factors, genetic buffering factors, environmental risk factors, and environmental buffering factors. To increase complexity even more, you can throw in epigenetic factors. In the past, we were limited in being able only to identify environmental risk and buffering factors. Now we can add to that mix the ability to at least quantify genetic risk (and our confidence in doing that will increase with increasing sample size). We still do not have a handle on genetic buffering factors. It is entirely possible that someone with high genetic risk for anorexia nervosa never develops the illness—due to the presence of genetic and/or environmental buffering factors. Likewise, someone with low genetic risk for anorexia nervosa could develop the illness in the presence of overwhelmingly risky environmental factors. So, neither genetics nor environment is destiny. Parents with histories of eating disorders who are struggling to figure out what the appropriate level of vigilance is as they watch their children traverse the ages of risk for eating disorders are encouraged to visit a genetic counselor. In the past genetic counselors focused primarily on diseases like Huntington’s where the probabilities of transmission were clear. They are now skilled in dealing with more complex diseases like anorexia nervosa and can aid families in understanding and apprising risk.  In general, we encourage parents to aim for a gentle balance between being hypervigilant versus blind to emerging signs of an eating disorder. If you are concerned about your child, the best option is to schedule an evaluation and speak with your provider about your concerns and how best to address them. This is an active area of research in the field and we hope to provide additional tools and guidance for parents in the near future.

Once again, we are grateful for all patients, family members, clinicians, advocates, and researchers who participated in ANGI. This has been a remarkable journey and we look forward to teaming up with you again when we roll out our next study, the Eating Disorders Genetics Initiative (EDGI). Stay tuned!

by Cynthia M. Bulik, PhD

This is the first of a four-part blog series discussing the results and process of ANGI and our planned next steps in studying the genetics of eating disorders.

We are thrilled to report that the work of the Anorexia Nervosa Genetics Initiative has come to fruition! Our paper entitled, “Genome-wide Association Study Identifies Eight Risk Loci and Implicates Metabo-Psychiatric Origins for Anorexia Nervosa” was published in the journal Nature Genetics on July 15, 2019. From what we can tell, this is the first time that an empirical paper on eating disorders has been published in that august journal. Our results are intriguing and encourage us to rethink how we conceptualize anorexia nervosa.

ANGI is an initiative of The Klarman Family Foundation. Our work began in January 2013, and the four ANGI sites (University of North Carolina at Chapel Hill; Karolinska Institutet, Stockholm, Sweden; Aarhus University, Aarhus, Denmark; and Berghofer Queensland Institute for Medical Research, with assistance from the University of Otago in Christchurch, New Zealand), we collected DNA samples from 13,363 individuals who had suffered from anorexia nervosa at some point in their lives, together with control individuals who were matched on ancestry and geography. Part 2 of this blog series explains more about how global cooperation made ANGI a success!

As described in a previous post on Exchanges, ANGI was designed to be a genome-wide association study or GWAS. GWAS are discovery science—meaning that you do not have to have any prior guesses about what you are looking for on the genome, you just let the genome speak for itself. GWAS scan the entire genome for over 1 million genetic markers and compare the genomes of thousands, tens of thousands, and even hundreds of thousands of cases (in ANGI, that is people with anorexia nervosa) to the genomes of as many controls. Even though it is a massive undertaking to collect such large samples of individuals, GWAS are the preferred method for examining the genetic underpinnings of psychiatric disorders.

Now to the results. We combined all of the ANGI samples with other samples that were available as part of the Eating Disorders Working Group of the Psychiatric Genomics Consortium. Briefly, we conducted a genome-wide association study (GWAS) comparing the whole genomes of 16,992 individuals with anorexia nervosa and 55,525 controls from 17 countries across the United States, Australasia, and Europe.

Members of the PGC Eating Disorders Workgroup meeting in Glasgow

The first exciting finding was that we identified 8 regions on the genome that were significantly associated with anorexia nervosa, on chromosomes (nearest gene) 1 (PTB2), 2 (ASB3, ERLEC1), 3 (FOXP1 and NSUN3), 5 (CHD10), 10 (MGMT), and 11 (CADM1). Although exciting, this is only the beginning, as we expect hundreds of genes to be implicated in risk for anorexia nervosa. But it also shows how important sample size is for gene discovery, as our previous study with a much smaller sample, only identified one area of the genome. If we look at progress in other psychiatric disorders, we believe that we have reached an inflection point, meaning that from this point forward as we increase samples size, gene discovery will accelerate.

Perhaps the most revolutionary findings of this study are not in the gene discovery per se, but rather in the pattern of genetic correlations that we observed with other traits and disorders. Genetic correlations (meaning some of the same genes are operative) reveal associations between traits. Our results indicate that:

• The genetic basis of anorexia nervosa overlaps with other psychiatric disorders such as obsessive-compulsive disorder, depression, anxiety, and schizophrenia.
• Genetic factors associated with anorexia nervosa also influence physical activity, which could help explain the tendency for people with anorexia nervosa to be highly active.
• Intriguingly, the genetic basis of anorexia nervosa overlaps with metabolic (including glycemic), lipid (fats), and anthropometric (body measurement) traits, and the study shows that this is not due to genetic effects that influence BMI.

In fact, this pattern of correlations led us to conclude that anorexia nervosa may best be conceptualized as a ‘metabo-psychiatric disorder’ and that it will be important to consider both metabolic and psychological risk factors when exploring new avenues for treating this potentially lethal illness.

To many of us, this comes as validation of what we have suspected for decades. Many of the perplexing behaviors associated with anorexia nervosa have been explained away as either psychological phenomena or by-products of starvation. When we see someone with anorexia at very low body weight out taking a run, we assume that it is driven by the desire to lose weight. Although it may be on the psychological level, we now know that it may also have a genetic origin, as some of the same genes that influence risk for anorexia also are associated with high physical activity. Likewise, when we see someone tragically lose weight after discharge from hospital after inpatient renourishment, we typically attribute it to drive for thinness or even denial of illness. While these things may be true, we may be missing the metabolic component of the illness. Perhaps a dysregulated metabolism is why individuals with anorexia nervosa can lose so much weight in the first place, when weight loss is so difficult for the majority of the people in the world. We have speculated that starvation and weight loss feel different to people who are genetically at risk for anorexia nervosa. Whereas to most people those are deeply unpleasant experiences, for many people with anorexia, they claim that starvation and low weight are associated with being less anxious and actually feeling better physically. In fact, may patients say that they begin to feel worse when they gain weight. Perhaps a greater focus on understanding the metabolic aspects of the illness will allow us to develop more effective interventions that are acceptable to patients and have enduring effects.

We don’t know what the metabolic factors are yet, but our results strongly encourage research that addresses that question. Our results may also explain the importance of adequate renourishment when we treat anorexia nervosa. Family Based Treatment (FBT) for youth with anorexia focuses strongly on renourishment. Inpatient renourishment is often most ineffective when we are forced to discharge patients (usually due to insurance denials) before they have reached a healthy weight. Perhaps one of the reasons this happens is that we are not giving their metabolisms an opportunity to reset after prolonged dysregulation.

It is often said that good science raises more questions than it answers, but at least in this case, our results are telling us which next questions we should address. Our findings strongly encourage us to augment our current focus with more detailed explorations of metabolic factors in the hope that such a focus will improve track record among health professionals in treating this pernicious illness.

ANGI is an important beginning, but it is just a beginning. Believe it or not, our sample size is still fairly small. Our colleagues studying depression already have over 250,000 participants, and geneticists studying height and weight have over 750,000! But now we know how to do this and have a blueprint for success. Stay tuned for Part 2 of this series to describe the study in detail, Part 3 in this series for an interview with Professor Patrick Sullivan on next steps, and Part 4 for personal reflections and what ANGI results mean for patients, families, and clinicians today.

Most importantly, heartfelt thanks to every person around the world who contributed their blood and clinical information to us in order to make ANGI a success. We felt, and we hope that you felt, a sense of community around our effort to achieve our scientific goals. We could never have produced this novel understanding of anorexia nervosa without your willingness to engage with us and become part of the ANGI team. Thank you for joining us on this journey of discovery.