The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome
10p1112, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of -aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-
control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) 61450 C>A and 83897 T>A (OR 0.81, 95 CI 0.6810.972, p 0.0049) and an at-risk SNP (243 A>G) for morbid obesity (OR 1.3, 95 CI 1.0531.585, p 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP 61450 C>A and 83897 T>A haplotype (2 7.637, p 0.02). In the murine insulinoma cell line TC3, the G at-risk allele of SNP 243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The 243 A>G SNP was
associated with higher hunger scores (p 0.007) and disinhibition scores (p 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic cells, we analyzed GAD65 antibody level as a marker of -cell activity and of insulin secretion. In the control group, 243 A>G, 61450 C>A, and 83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP 83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B homeostasis model of -cell function (p 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.