Anorexia nervosa is a multifactorial neuropsychiatric condition that affects as many as one percent of women in the Western world, and has an estimated mortality as high as 10 percent, making it perhaps the deadliest of mental illnesses. Anorexics severely restrict eating and become emaciated, yet consider themselves overweight. Individuals with anorexia tend to be perfectionistic, anxious or depressed, and obsessive.
The largest DNA-sequencing study of anorexia nervosa to-date has linked the eating disorder to variants in a gene coding for an enzyme that regulates cholesterol metabolism, which suggests to the researchers that anorexia could be caused, in part, by a disruption in the normal processing of cholesterol, which may disrupt mood and eating behavior. How the disorder develops is unknown but anorexia predominantly affects girls and young women (by a ratio nearly 10:1) in developing nations and thus appears to be influenced by cultural factors. Yet some twin studies have suggested that genetic factors have a large influence.
If so, what are those genetic factors? Gene-association studies of anorexics have so far produced few replicable findings. Researchers suspect that many genes can contribute to the disorder and thus only large studies will have the statistical power to detect those individual genetic influences.
To accomplish the largest-ever sequencing study of anorexia, the researchers made use of genetic information from more than 1,200 anorexia patients and nearly 2,000 non-anorexic control subjects. For an initial “discovery” study in 334 subjects, the researchers cataloged the variants of a large set of genes that had already been linked to feeding behavior or had been flagged in previous anorexia studies. Of more than 150 candidate genes, only a handful showed statistical signs of a linkage with anorexia in this group of subjects.
One of the strongest signs came from the gene EPHX2, which codes for epoxide hydrolase 2—an enzyme known to regulate cholesterol metabolism. “When we saw that, we thought that we might be onto something, because nobody else had reported this gene as having a pronounced role in anorexia,” said said Nicholas J. Schork, a professor at The Scripps Research Institute (TSRI) and senior investigator for the study.
The team followed up with several replication studies, each using a different cohort of anorexia patients and controls, as well as different genetic analysis methods. The scientists continued to find evidence that certain variants of EPHX2 occur more frequently in people with anorexia.
To help make sense of these findings, they looked at existing data from a large-scale, long-term heart disease study and determined that a subset of the implicated EPHX2 variants have the effect of altering the normal relationship between weight gain and cholesterol levels.
“We thought that with further studies this EPHX2 finding might go away, or appear less compelling, but we just kept finding evidence to suggest that it plays a role in anorexia,” said Schork.
It isn’t yet clear how EPHX2 variants that cause an abnormal metabolism of cholesterol would help trigger or maintain anorexia. But Schork noted that people with anorexia often have remarkably high cholesterol levels in their blood, despite being severely malnourished. Moreover, there have been suggestions from other studies that weight loss, for example in people with depression, can lead to increases in cholesterol levels. At the same time, there is evidence that cholesterol, a basic building block of cells, particularly in the brain, has a positive association with mood. Conceivably, some anorexics for genetic reasons may feel an improved mood, via higher cholesterol, by not eating.
“The hypothesis would be that in some anorexics the normal metabolism of cholesterol is disrupted, which could influence their mood as well as their ability to survive despite severe caloric restriction,” said Schork.
For now that’s just a hypothesis, which Schork emphasized should be investigated further with more gene association studies and more studies of EPHX2 variants’ biological effects.
Citation: A A Scott-Van Zeeland, C S Bloss, R Tewhey, V Bansal, A Torkamani, O Libiger, V Duvvuri, N Wineinger, L Galvez, B F Darst, E N Smith, A Carson, P Pham, T Phillips, N Villarasa, R Tisch, G Zhang, S Levy, S Murray, W Chen, S Srinivasan, G Berenson, H Brandt, S Crawford, S Crow, M M Fichter, K A Halmi, C Johnson, A S Kaplan, M La Via, J E Mitchell, M Strober, A Rotondo, J Treasure, D B Woodside, C M Bulik, P Keel, K L Klump, L Lilenfeld, K Plotnicov, E J Topol, P B Shih, P Magistretti, A W Bergen, W Berrettini, W Kaye and N J Schork, 'Evidence for the role of EPHX2 gene variants in anorexia nervosa', Molecular Psychiatry 3 September 2013 doi: 10.1038/mp.2013.91
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