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The largest DNA-sequencing study of anorexia nervosa has linked the eating disorder to variants in a gene coding for an enzyme that regulates cholesterol metabolism. The finding suggests that anorexia could be caused in part by a disruption in the normal processing of cholesterol, which may disrupt mood and eating behavior.
“These findings point in a direction that probably no one would have considered taking before,” said Nicholas J. Schork, a professor at The Scripps Research Institute (TSRI). Schork was the senior investigator for the multicenter study, which was published recently online ahead of print in the journal Molecular Psychiatry.
Individuals with anorexia nervosa tend to be perfectionistic, anxious or depressed, and obsessive, said 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.
How the disorder develops is still not fully understood.
The big mystery has been: 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.
For this project—the largest-ever sequencing study of anorexia—Schork worked with an international team of collaborators representing more than two dozen research institutions. The project made use of genetic information from more than 1,200 anorexia patients and nearly 2,000 non-anorexic control subjects.
“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 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,” 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.
The study was funded principally by the Price Foundation of Switzerland. “It was a long and difficult study and the foundation was very gracious and patient, and that was important,” Schork said.
The many contributors included first author Ashley Scott-Van Zeeland from The Scripps Translational Science Institute and Scripps Health in La Jolla, California; Kaye and Pei-an Betty Shih from the UC San Diego; Andrew Bergen from SRI International in Menlo Park, California; Wade Berretini from the University of Pennsylvania; and Pierre Magistreti from Ecole Polytechnique Fédérale de Lausanne.
Other funding came from the National Institutes of Health (e.g., grant 5 UL1 RR025774). For more information, see http://www.nature.com/mp/journal/vaop/ncurrent/abs/mp201391a.html
In addition to Schork, Kaye, Scott-Van Zeeland, Shih, Bergen, Berretini and Magistreti, contributors to the study, “Evidence for the role of EPHX2 gene variants in anorexia nervosa,” about 40 other scientists from: The Scripps Translational Science Institute of TSRI and Scripps Health (La Jolla, California); UC San Diego; Tulane University (New Orleans, Louisiana); University of Maryland School of Medicine (Baltimore); University of Minnesota, Minneapolis; Roseneck Hospital for Behavioral Medicine (Prien, Germany); Weill Cornell Medical College (White Plains, New York); Eating Recovery Center (Denver, Colorado); Center for Addiction and Mental Health (Toronto, Canada); Toronto General Hospital, University Health Network (Toronto, Canada); University of North Carolina at Chapel Hill (Chapel Hill, NC); Neuropsychiatric Research Institute (Fargo, North Dakota); David Geffen School of Medicine, University of California, Los Angeles: University of Pisa (Italy); Guys Hospital, University of London (UK); Florida State University, Tallahassee; Michigan State University, East Lansing; Argosy University (Washington, DC); University of Pittsburgh; University of Lausanne, Switzerland; SRI International (Menlo Park, CA); University of Pennsylvania, Philadelphia.
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Original press releas: http://www.scripps.edu/news/press/2013/20130911schork.html