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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
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Home | Pregnancy Timeline | News Alerts |News Archive Sep 12, 2013

 

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International Study Provides New Genetic Clue to Anorexia

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.


Anorexia affects up to 1 percent of women, and has an estimated mortality rate of 10 or more percent, making it perhaps the deadliest of psychiatric illnesses. Anorexics severely restrict eating and become emaciated, yet see themselves as fat.


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.


Anorexia predominantly affects girls and young women (the estimated gender ratio is nearly 10:1) and appears to be influenced in part by cultural factors, stress, puberty and social networks.

Yet twin studies suggest that genetic factors have the largest influence.


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.


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,” 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.


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.”

Nicholas J. Schork, professor, The Scripps Research Institute


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.

Abstract
Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric conditions with likely rare and common genetic and environmental determinants. To identify genetic variants associated with AN, we pursued a series of sequencing and genotyping studies focusing on the coding regions and upstream sequence of 152 candidate genes in a total of 1205 AN cases and 1948 controls. We identified individual variant associations in the Estrogen Receptor-ß (ESR2) gene, as well as a set of rare and common variants in the Epoxide Hydrolase 2 (EPHX2) gene, in an initial sequencing study of 261 early-onset severe AN cases and 73 controls (P=0.0004). The association of EPHX2 variants was further delineated in: (1) a pooling-based replication study involving an additional 500 AN patients and 500 controls (replication set P=0.00000016); (2) single-locus studies in a cohort of 386 previously genotyped broadly defined AN cases and 295 female population controls from the Bogalusa Heart Study (BHS) and a cohort of 58 individuals with self-reported eating disturbances and 851 controls (combined smallest single locus P<0.01). As EPHX2 is known to influence cholesterol metabolism, and AN is often associated with elevated cholesterol levels, we also investigated the association of EPHX2 variants and longitudinal body mass index (BMI) and cholesterol in BHS female and male subjects (N=229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (P<0.01). These findings suggest a novel association of gene variants within EPHX2 to susceptibility to AN and provide a foundation for future study of this important yet poorly understood condition.

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.

About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

Original press releas: http://www.scripps.edu/news/press/2013/20130911schork.html