Could new genetic studies unlock the mysteries of eating disorders? I ask Dr Cynthia Bulik about exciting developments in this field, and she explains how your DNA could be a piece of the puzzle

    AM: After the results of the 2019 Anorexia Nervosa Genetics Initiative (ANGI) study, is it possible to say definitively that there is a genetic element to anorexia nervosa? And does this mean that you can only develop the disorder if you have the genetic predisposition?

    CB: We have actually been quite confident that there is a genetic component to AN for quite a while (looking back to the many replicated twin studies that convincingly showed that genes played a role). Of course a genome-wide association study gets us closer to the biology than twin studies do, so we are really in the next stage of the science in which we are working toward identifying actual gene variants, and gene pathways that influence the disorder. So we really shouldn’t be debating anymore whether genes play a role.

    It does not mean that you can only develop the disorder if you have a genetic disposition. Remember, AN is a complex trait meaning that it is influenced by hundreds, maybe even thousands, of genes of small effect along with environmental factors. It is better to talk about how strong your genetic predisposition is and how strong your environmental risk factors are. We presume (and are studying) whether individuals who have fairly low genetic risk for AN, but who have the disorder, might report more environmental risk factors. In comparison, someone with very high genetic risk for AN might need very little prodding from the environment for their genetic predisposition to be expressed.

    AM: Anorexia nervosa was not always considered a purely psychological illness. In previous centuries physicians considered the biological aspect of the condition too (I look at the history of anorexia nervosa here ). But since the beginning of the last century, most people thought of anorexia as a psychosocial disorder. What caused you to start looking at anorexia differently, at the biology of the illness and in particular the possibility that there might be a link to a person’s genetics?

    CB: You are correct! In fact, the core of the illness hasn’t changed for centuries. Detailed descriptions of, for example of St Catherine of Siena, reveal a strikingly similar picture to what we see today clinically, but the ‘sociocultural packaging’ was different. Then the packaging was about purity, holiness, being closer to God, now it is more about the socially mandated drive for thinness. I think this particular type of packaging caught on because it had face validity—people looked at ultra-thin models and they looked at people with AN and it seemed like a logical progression. They failed to realise that AN goes far beyond what one sees in a magazine, and that many models themselves have eating disorders. It is a hard perception to push back though because it just ‘makes sense’ to people. Many patients scoff at this comparison because it misses the boat so much.

    ‘the magnitude of the correlation with metabolic traits was as impressive’

    AM: You have said that anorexia should be reclassified as a metabo-psychiatric disorder. Could you explain what led you to this conclusion? Do you now know exactly how the metabolism of someone with anorexia is affected? And is it possible that future treatments could target metabolism, perhaps with pharmaceuticals?

    CB: We said ‘re-conceptualized’ not reclassified as such a classification doesn’t actually exist anywhere. We noted this because of the strong genetic correlations that we saw between AN and various metabolic and anthropometric traits. We very much expected there to be high genetic correlations with other psychiatric disorders (like OCD, depression), but the magnitude of the correlation with metabolic traits was as impressive. This means that some of the same genes are operative in AN as in other psychiatric disorders (having effects in the same direction, or increasing risk for both) and some of the same genes are operative in AN as in various metabolic and anthropometric traits (BMI, waist to hip ratio, lipids, insulin) but the effects are in opposite directions. So, genes that make you more likely to develop AN, make you less likely to have a high BMI (for example).

    AM: The genetics studies you have been involved in show that there is a crossover with other mental illnesses, including schizophrenia, anxiety and OCD. Does this mean that we should be trialling treatments for these conditions on people with anorexia and vice versa? For example, medications for schizophrenia for people with anorexia or weight gain for people diagnosed with OCD?

    CB: Interestingly, the genetic correlations that we saw very much parallel what we see clinically (high correlation with OCD, depression, anxiety). Schizophrenia was less obvious as we don’t see that comorbid pattern as frequently. One of our recent PhD students has just published a series of papers looking at the association between EDs and schizophrenia, trying to dig deeper into what the association means. Many medications that have been successful in OCD and schizophrenia have been tried in AN and results have not been convincing. Perhaps it is because they tap into the shared psychological features, but not the metabolic features that might also be awry.

    AM: In your reflections on the 2019 study, you described some of the mysteries that surround anorexia. Has there been any progress on answering any of these questions?

      1. How do people with this illness reach and maintain such low weights?

      2. Why is negative energy balance reinforcing for them?

      3. Why does their weight fall so quickly even after medically-supervised re-nourishment?

      4. Why does physical activity seem to be more reinforcing than food?

    CB: We are actually doing a very interesting study in Sweden right now in which we selected individuals with AN who participated in a genetic study based on their degree of genetic risk (technically the top ten per cent and the bottom ten per cent of genetic risk). Our psychologists developed an in-depth interview that delves into the experience of negative energy balance and other aspects of the experience of having AN (the mysteries in bullet points above). 19/20 interviews are done and 19 have been transcribed and now the hard part starts with coding the interviews using qualitative analysis approaches. We hope to have some very interesting results over the next few months that we will be able to share with the world.

    ‘we really need a universal definition of recovery’

    AM: You’ve suggested that many treatment programs stop the weight restoration process too early. I agree, and talk about my family’s experience of this in this post . Does this mean much of the published research on treatment is suspect, given that they might use a deficient definition of recovery?

    CB: Not necessarily. In some studies, duration of treatment is not limited by the insurance company deciding that it is time for them to go home. The pressure to discharge patients prematurely from treatment is largely driven by the insurance industry. In countries where this is not a problem, they have more of a luxury to keep people in treatment longer. However, we really need a universal definition of recovery so that we actually can compare outcomes across studies (and across programs). Very few programs disclose their outcome data and there aren’t really standards of care that insurance companies hold them to (see the commentary that Walt Kaye and I did in JAMA Psychiatry).

    AM: Do you know if any research has considered low core body temperature as a cause rather than a symptom in anorexia nervosa? We know that the human body normally maintains a near-constant average core temperature of 37ºC. If this falls to, say, 36ºC, for a sustained period (because of negative energy balance), what effect might this have on the brain? Some of the initial signs of hypothermia (body temperature lower than 35ºC) are: difficulties with decision making and uncharacteristic irritability—similar to some of the early signs of anorexia nervosa. Could a slightly reduced average core temperature (36ºC) affect brain function in people susceptible to anorexia nervosa?

    CB: I think this is a super interesting question and honestly I have not read much of anything about it. I am going to see if we can add this to one of our studies and it would also be really interesting to look at people who have recovered from AN to see if they continue to have lower body temperature (ie, a trait effect rather than a state effect). I know one of the groups in Stockholm has used warming approaches with their patients and they have published a few papers on it, but I haven’t read anything on low temperature being causal rather than a symptom of starvation.

    ‘many genes and many environmental factors of small to moderate effect combine to risk’

    AM: I think it’s important to state that genetics don’t equal destiny and that if you have a predisposition you can still make a full recovery. I have identical twin daughters who both developed anorexia nervosa at roughly the same time. While one made a rapid recovery, the other did not recover and is still unwell, six years on. Do you have any answers as to why some people might be more resilient to the condition, even when they share the same genes?

    CB: This gets back to my comment about many genes and many environmental factors of small to moderate effect that combine to risk. Even though your daughters are monozygotic (MZ) twins and share on average 100 per cent of their genes, that does not mean that their gene expression is identical, nor does it mean that they were exposed to the exact same environmental factors. Even in the uterus, their environments weren’t identical—if they had one sac or two, if one received more nutrients than the other, all the way up through the experiences they had in school and random things that happened to one and not the other (the slings and arrows of outrageous fortune as Shakespeare said). We’re actually partway through a really interesting study called CREAT in Sweden in which we are studying MZ twins who are discordant for AN (so unlike your daughters one had AN and the other did not) compared to MZ twins neither of which had AN.

    ‘the largest genetic study of eating disorders ever undertaken’

    AM: Finally, can you tell us a little about the Eating Disorders Genetics Initiative (EDGI) project and how people can get involved?

    CB: EDGI is the largest genetic study of eating disorders ever undertaken and we are growing every day! The National Institute of Mental Health has funded sites in the US (based at the University of North Carolina), New Zealand, Australia, and Denmark and we have brought other partners on board and identified funding and resources to increase the diversity of our sample and our global reach. We now have parallel studies underway in Sweden, the UK, Mexico, Italy, the Netherlands and are gearing up for Taiwan, Canada, Spain and hopefully other countries as well. EDGI goes beyond ANGI (which was only anorexia nervosa) to now include AN, bulimia nervosa, and binge-eating disorder. Some countries are also able to include other presentations like atypical AN, and we are all hoping to include ARFID soon.

    Participation is quite easy, just go up to the website, take the survey and then, if you meet the criteria set out by whichever country you are living in, there are more questionnaires to complete (depression, anxiety, physical activity, life events) and a very simple saliva sample that, when it comes in the post, you just follow the instructions, spit, and send it right back! Super simple, Covid safe and you become part of a global community of scientists and people with lived experience coming together to figure out the causes of these illnesses and how to drive more effective and enduring treatments to improve the lives of those with eating disorders.

    Dr Cynthia Bulik is the Founding Director of the University of North Carolina Center of Excellence for Eating Disorders and the founder and director of the Centre for Eating Disorders Innovation at Karolinska Institutet in Stockholm, Sweden. Her clinical work and research on eating disorders span decades and continents

    Is there a genetic component to anorexia?
    Although thought of as a psychological problem, the eating disorder anorexia nervosa often runs in families, suggesting that it has a genetic component. Now researchers have found two genes that help determine the risk of acquiring the disease. more
    Does anorexia cause diabetes?
    While anorexia isn't shown to increase the odds that you or your loved one will develop diabetes, this mental health condition is serious and requires treatment. more
    Is anorexia always fatal?
    The findings show anorexia to be the most deadly psychiatric diagnosis. The anorexia mortality rate of 5.86 is dramatically higher than: Schizophrenia, which increases death risk 2.8-fold in males and 2.5-fold in females. Bipolar disorder, which increases death risk 1.9-fold in males and 2.1-fold in females. more
    What is secondary anorexia?
    Secondary anorexia is one of the main factors responsible for the development of malnutrition, which in turn negatively affects patient morbidity and mortality. Different mechanisms have been proposed to explain the pathogenesis of secondary anorexia. more
    What medications cause anorexia?
    List of Drugs that may cause Anorexia (Loss Of Appetite)
    • Acetaminophen and Codeine.
    • Acetazolamide.
    • Anagrelide.
    • Biperiden.
    • Bosentan.
    • Calcium Phosphate.
    • Carbidopa-Levodopa.
    • Clopamide.
    What is restrictive anorexia?
    A person with the restricting subtype of anorexia nervosa severely restricts energy intake and weight loss occurs primarily through dieting, fasting and/or excessive exercise. more
    What is the difference between anorexia athletica and anorexia nervosa?
    Anorexia athletica is used to refer to "a disorder for athletes who engage in at least one unhealthy method of weight control". Unlike anorexia nervosa, anorexia athletica does not have as much to do with body image as it does with performance. more
    What is emotional anorexia?
    Emotional anorexia means that you are living in emotional starvation mode. Just as irritability and anger happen when your blood glucose levels go down, when you don't have enough “psychological sugar” your emotional “blood levels” also go down. more
    Does anorexia affect height?
    While anorexia might be expected to cause short stature, and some studies suggest that girls with the eating disorder are indeed shorter than normal, other research suggests they may reach their full height potential, or even be taller than average. more
    What's the difference between anorexia and anorexia?
    "Anorexia" describes a simple inability or aversion to eating, whether caused by a medical problem or a mental health issue. "Anorexia nervosa," however, is the name for the clinical eating disorder, the main symptom of which is self-starvation. more
    Can MRI detect anorexia?
    Investigating the brain of patients with anorexia nervosa, structural and functional changes can be detected [6]. In MRI scans the most common finding is gray and white matter reduction correlating with the extent of malnourishment and mostly reversible with recovery and weight normalization [7]. more


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