The role of genetic factors in common obesity is complex, and the identification of candidate genes is complicated by both the polygenic nature of the disease and the fact that affected families tend to share lifestyle habits. Independent linkage studies in different populations have demonstrated strong linkage between a region of chromosome 10, containing the GAD2 gene that encodes the glutamic acid decarboxylase enzyme (GAD65), and obesity. The GAD65 enzyme catalyses the production of the neurotransmitter gamma-amino butyric acid (GABA) that helps stimulate appetite through interaction with a neuropeptide (NPY) in the hypothalamus.
A recent study by Froguel and colleagues has suggested GAD2 as a candidate gene for human obesity [Boutin, P. et al. GAD2 on chromosome 10p12 is a candidate gene for human obesity. PLos Biology 1(3) E-Pub 2003 Nov 3 DOI: 10.1371/journal.pbio.0000020 http://www.plosbiology.org/pips/plbi-01-03-froguel.pdf]. This study was also the subject of a report in the Guardian (November 3rd, 2003). In a case (n=575)-control (n=646) study in French Caucasian adults they found a single nucleotide polymorphism (SNP) –243 A>G to be associated with morbid obesity (odds ratio[OR]: 1.3, 95% confidence interval [95% CI]= 1.05-1.59; p=0.014). In addition, a haplotype including the SNPs +61450 C>A and +83897 T>A was found to confer a protective effect against obesity in both the case-control (OR=0.81; 95%CI= 0.68-0.97; p=0.005) and familial-based analyses (chi-squared= 7.64, p=0.02). Using a standardised assessment of eating behaviour, the authors found that among morbidly obese individuals those heterozygous (GG) at the –243 SNP had significantly more difficulty controlling their food intake. In contrast, the haplotype containing the wild-type alleles (A, C, and T) for the SNPs –243 A>G, +61450 C>A, and +83897 T>A was significantly associated with a lower hunger score than the variant alleles. When investigating the physiological effect of the GAD2 high-risk alleles in a mouse cell line, the authors found that the –243 G/G construct caused a six-fold increase in transcriptional activity compared to the wild-type –243 A/A variant.
The authors suggest that overexpression of GAD2 may increase the concentration of the neurotransmitter GABA in the hypothalamus, resulting in an up-regulation of the effect of GABA leading to overeating. This relatively large study provides initial data to suggest that GAD2 may be a candidate gene for obesity. However, given the polygenic nature of obesity, and the interaction with environmental factors such as diet, further work will be required to fully determine the precise role of GAD2 in the aetiology of obesity.