Next-gen DNA sequencing helps provide new genetic clue to anorexia

The largest next-generation 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. The multicenter study, led by Nicholas J. Schork, a professor at The Scripps Research Institute (TSRI; La Jolla, CA), suggests that anorexia could be caused in part by a disruption in the normal processing of cholesterol, which may disrupt mood and eating behavior.

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Schork worked with an international team of collaborators representing more than two dozen research institutions. The study 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 catalogued 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,” says Schork.

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,” says Schork.

It isn’t yet clear how EPHX2 variants that cause an abnormal metabolism of cholesterol would help trigger or maintain anorexia. But Schork notes 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, e.g., 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,” says Schork.

For now that’s just a hypothesis, which Schork emphasizes should be investigated further with more gene association studies and more studies of EPHX2 variants’ biological effects.

Contributors included first author Ashley Scott-Van Zeeland from The Scripps Translational Science Institute and Scripps Health (also in La Jolla); Walter Kaye, a co-author on the study, professor at the University of California (UC) San Diego School of Medicine and principal investigator of the Price Foundation Genetic Studies of Anorexia Nervosa; Pei-an Betty Shih of UC San Diego; Andrew Bergen from SRI International (Menlo Park, CA); Wade Berretini from the University of Pennsylvania; and Pierre Magistreti from École Polytechnique Fédérale de Lausanne (Switzerland).

The study was funded principally by the Price Foundation of Switzerland. Full details of the work appear online ahead of print in the journal Molecular Psychiatry; for more information, please visit http://www.nature.com/mp/journal/vaop/ncurrent/abs/mp201391a.html.

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