Edited by Laurel Mayer, MD, and B. Timothy Walsh, MD.
Metabo-psychiatric? What does that mean? Metabolism refers to the processes relevant to energy and other chemical changes needed by living organisms. The term psychiatric means relating to mental illness or its treatment.
That anorexia nervosa is a psychiatric problem – a problem of the mind — has long been recognized. A central feature of the disorder is that low weight or weight loss is, at least in part, caused by an intense fear of being fat or weight gain, or behavior that gets in the way of maintaining healthy weight.
In the low weight state, however, metabolism is impacted in several ways. Though this has received some attention as a consequence of the disorder, researchers have recently been asking questions about whether there are ways in which an individual’s metabolic hardwiring increases risk for anorexia nervosa. A recent study published in Nature Genetics calls for a reconceptualization of anorexia nervosa as a “metabo-psychiatric” disorder, and here at Columbia, we are thinking hard about this idea. Here is a brief overview of the study, and what we are learning from it.
The study, conducted by a team of investigators at the University of North Carolina Chapel Hill in collaboration with authors at over 174 institutions, was published in Nature Genetics in August 2019.
The study first examined hundreds of thousands of genetic variants (“single nucleotide polymorphisms” or “snps”) to identify those that might be associated with risk for anorexia nervosa. SNPs are like flags or zip codes. They themselves are not the gene, but they travel with the gene and let you know you may be near an important gene. Although similar studies had been done before, the samples sizes of prior studies were relatively small. This study pooled samples from more than 30 prior studies (which included over 70,000 people – about 17,000 who had anorexia nervosa), giving it greater ability to detect an effect of a genetic variant on illness risk.
Researchers then compared these anorexia nervosa-linked genes with genes that had been previously found to predict other traits and psychiatric disorders. They used a sophisticated program to figure out if the anorexia nervosa genes were the same genes that are linked with other traits, termed genetic correlation. Genetic correlation is the proportion of variability shared by two traits due to genetics.
There were two primary findings from this study:
- The first was the identification of 8 loci (specific spots on chromosomes) associated with an increased risk of anorexia nervosa.
- There were significant positive genetic correlations between anorexia nervosa and other psychiatric disorders (such as depression and obsessive-compulsive disorder), education, and HDL (“good”) cholesterol. There were also significant negative genetic correlations with body mass index, other body composition measurements (like lean and fat mass), and some indices of insulin sensitivity and diabetes.
What does (and doesn’t) it mean?
The identification of 8 new snps.
This study reported 8 genetic loci were above the significance threshold (-log10 (P)>7.3), but it was the ones on chromosome 3 and 11 that were well above the threshold, and therefore considered more robust findings.
The snp on chromosome 3 was associated with 111 genes, but the snp on chromosome 11 was associated with a single gene. 111 genes are a lot to sort through to find the one target that might be a key to anorexia nervosa. Also, all together, the genes with known associations to anorexia nervosa only explained about 1-2% of the variability in whether someone develops the disease, and each individual gene explains far less. This means that there are a lot of steps between identifying a snp and identifying the genetic cause of this illness.
Genetic correlations between anorexia nervosa and other traits and disorders.
Genetic correlations between anorexia nervosa and anxiety, major depression, and obsessive-compulsive disorder add to an expanding literature supporting common genetic underpinnings of this eating disorder and other psychiatric disorders.
Although low BMI is a known consequence of anorexia nervosa, we wondered whether these results suggested that there might be a genetic basis making it physiologically “easier” for individuals with anorexia nervosa to have a low BMI. But as we discussed the findings in more detail, we were reminded that genetic associations are not the same as identifying causation or mechanism. It is not surprising, and perhaps even reassuring, that genes associated with weight regulation would also be associated with the disorder.
Understanding if and how metabolic processes contribute to onset or maintenance of anorexia nervosa is an important direction. Even though genes linked to metabolism were implicated in this study, this finding does not mean that people with anorexia have a “faster metabolism” that makes it harder to gain weight and keep it on. In other words, even though genetic correlations were seen between anorexia nervosa and metabolic processes involving glucose and insulin, this does not necessarily mean that they use calories at a different rate at rest.
From prior research, some of which was done at Columbia, we know a bit about other pieces of the metabolism puzzle. Dr. Laurel Mayer previously studied whether individuals with anorexia nervosa exhibited metabolic differences that leads them to lose and maintain low weight. Specifically, do their bodies burn more calories, making it harder to eat enough to maintain weight? The finding was no: Metabolically, people with the disorder were similar to those without anorexia nervosa who lost weight: At a low weight, resting metabolism slowed down. When weight was normalized, it returned to the expected level, but not higher.
We’re still a long way away from identifying the genes that cause anorexia nervosa, and this study is an important first step. Congrats to Drs. Watson and Bulik and their team!