GAD2 link to eating disorders

An international group of researchers has provided experimental evidence to suggest that the activity of a gene known as GAD2 is strongly related to eating disorders such as anorexia and obesity.

The study, published in the newly set-up free access Public Library of Science Biology​ journal, backs extends earlier research that found a link between GAD2, which appears on chromosome 10, and obesity.

The researchers, headed by Professor Philippe Froguel of the Pasteur Institute in Lille, France, note that GAD2 codes for an enzyme (glutamic acid decarboxylase, or GAD65) which catalyses the production of a gamma aminobutyric acid (GABA), one of the primary inhibitory neurotransmitters in the central nervous system. GAD65 in turn interacts with a neuropeptide (neuropeptide Y or NPY) in the hypothalamus to help stimulate appetite.

The hypothesis is that in individuals who maintain normal-range weight, there is a balance between those neuropeptides in the CNS that promote eating, and those that suppress it. Researchers believe that individuals with a more active form of the GAD gene accumulate a larger pool of GABA in the hypothalamus and generate an excess of NPY. This could explain why obese individuals overeat.

In the latest study, Froguel et al screened genomic data from 575 obese subjects and 646 controls for GAD2 alleles. They identified one groupof alleles as protective against obesity and another as increasing risk.

These links were supported by genetic screens of the nuclear families participating in the study, which revealed a higher frequency of the protective group of alleles in the controls. Obese individuals with two copies of one at-risk allele also had more difficulty controlling food intake compared to control subjects, based on a standardised assessment of eating behavior.

Moreover, when the researchers investigated the physiological effect of the ''highest risk ''GAD2 variant in a mouse cell line, they found it caused a six-fold increase in transcriptional activity compared to the 'wild-type' cells without the mutation.

Swedish company Diamyd Medical licenses the therapeutic applications of the GAD2 gene from the University of California in USA.

"As the company understands it, GAD gene therapy might be used for treatment of anorexia eating disorders,"​ said Diamyd's president, Anders Essen-Möller, although he declined to make any statements about the impact on the new research on the company.

While extreme obesity is thought to be the combined result of a variety of genetic and environmental factors, GAD2 is the first gene implicated as a strong factor in conditions of abnormal weight.