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Anorexia GWAS Yields Risk Loci with Metabolic, Psychiatric Overlap

NEW YORK – An international team led by investigators in the US, Sweden, and the UK has come up with evidence suggesting that genetic factors involved in psychiatric and metabolic traits may contribute to anorexia nervosa risk.

The researchers did a genome-wide association study involving nearly 17,000 cases and more than 55,500 controls, enrolled through almost three-dozen prior analyses. As they reported online today in Nature Genetics, their analysis led to eight new loci with significant ties to anorexia nervosa risk, including sites that overlapped with psychiatric, metabolic, and other conditions or traits.

Co-senior and corresponding author Cynthia Bulik, a psychiatry researcher affiliated with University of North Carolina, Chapel Hill and the Karolinska Institute, and her colleagues noted that such findings "encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder."

"Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes," she and her co-authors wrote, noting that the current findings "encourage consideration of both metabolic and psychological drivers of anorexia nervosa when exploring new avenues for treating this frequently lethal illness."

Anorexia nervosa is a potentially life-threatening condition characterized by a very low body mass index (BMI), distorted body image, and intense fear of gaining weight, the team explained. Results from twin studies suggest anorexia heritability is on the order of up to 50 or 60 percent, with past GWAS unearthing common risk variants that overlapped with psychiatric traits and possible metabolic or anthropometric traits.

"Low BMI has traditionally been viewed as a consequence of the psychological features of anorexia nervosa," the authors wrote, noting that "[t]his perspective has failed to yield interventions that reliably lead to sustained weight gain and psychological recovery."

In an effort to unearth previously unappreciated genetic contributors to the disease, members of the Anorexia Nervosa Genetics Initiative and the Psychiatric Genomics Consortium's Eating Disorders Working group compared genome-wide genotypes in 16,992 individuals with anorexia nervosa and 55,535 unaffected control individuals, all of European descent, analyzing both individual cohorts and performing a GWAS meta-analysis.

The team was left with genome-wide significant anorexia-associated variants at eight loci, and used a combination of expression quantitative trait locus clues, potential regulatory chromatin effects, and location to focus in on the PTBP2, ASB3/ERLEC1, NCKIPSD, FOXP1, NSUN3, CDH10, MGMT, and CADM1 genes on chromosomes 1, 2, 3, 5, 10, and 11. Even so, the analyses hinted that loci with genome-wide significant ties to anorexia had potential ties to many more genes that are expressed in the brain.

The researchers' multi-trait analysis, which considered significant anorexia-associated SNPs in the context of variants implicated in other traits and conditions, suggested that seven of the loci were independent. With their genetic correlation, systems biology, and gene expression analyses, meanwhile, they saw SNP overlap with everything from obsessive compulsive disorder, major depressive disorder, anxiety, or schizophrenia to physical activity, metabolic traits, BMI and other body features.

"The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid, and anthropometric traits independent of the effects of common variants associated with body mass index," they reported.

Such findings may help to explain how difficult it is to successfully treat anorexia nervosa, the authors suggested, hinting that genetically altered metabolic regulation may contribute to some of the problems faced by affected individuals when trying to keep on weight after re-nourishment therapy. 

"Metabolic abnormalities seen in patients with anorexia nervosa are most often attributed to starvation, but this study shows they may also contribute to the development of the disorder," co-senior author Gerome Breen, psychiatry, psychology, and neuroscience researcher at King's College London, said in a statement. "These results suggest that genetic studies of eating disorders may yield powerful new clues about their causes and may change how we approach and treat anorexia."