GAD2 on Chromosome 10p12 Is a Candidate Gene for Human Obesity

• Published in: PLoS biology Vol. 1; no. 3; p. e68
• Main Authors: Boutin, Philippe, Dina, Christian, Vasseur, Francis, Dubois, Séverine, Corset, Laetitia, Séron, Karin, Bekris, Lynn, Cabellon, Janice, Neve, Bernadette, Vasseur-Delannoy, Valérie, Chikri, Mohamed, Charles, M. Aline, Clement, Karine, Lernmark, Ake, Froguel, Philippe
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2003; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Alleles; Autoantibodies; Autoantibodies - chemistry; Body mass index; Case-Control Studies; Catalysis; Cell Line; chromosome 10; Chromosome Mapping; Chromosomes, Human, Pair 10; Chromosomes, Human, Pair 10 - genetics; Chromosomes, Human, Pair 10 - ultrastructure; Eating; Family Health; Feeding Behavior; Female; GAD2 gene; gamma-Aminobutyric Acid; gamma-Aminobutyric Acid - metabolism; Genes; Genetic Linkage; Genetics; Genetics/Genomics/Gene Therapy; Genotype; Glutamate Decarboxylase; Glutamate Decarboxylase - chemistry; Glutamate Decarboxylase - genetics; Glutamate Decarboxylase - physiology; Haplotypes; Homo (Human); Human genetics; Humans; Hunger; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells; Insulin-Secreting Cells - metabolism; Isoenzymes; Isoenzymes - chemistry; Isoenzymes - genetics; Isoenzymes - physiology; Life Sciences; Linkage (Genetics); Lod Score; Luciferases; Luciferases - metabolism; Male; Middle Aged; Minority & ethnic groups; Molecular Sequence Data; Neuropeptide Y; Neuropeptide Y - metabolism; Neuroscience; Obesity; Obesity - genetics; Obesity, Morbid; Obesity, Morbid - genetics; Odds Ratio; Paraventricular Hypothalamic Nucleus; Paraventricular Hypothalamic Nucleus - metabolism; Plasmids; Plasmids - metabolism; Polymorphism, Single Nucleotide; Promoter Regions (Genetics); Promoter Regions, Genetic; Questionnaires; Risk; Rodents; Surveys and Questionnaires; Haplotypes; Humans; Middle Aged; Molecular Sequence Data; Family Health; Male; Risk; Case-Control Studies; Lod Score; Hunger; Obesity, Morbid; Luciferases; Questionnaires; Adult; Female; Catalysis; Insulin-Secreting Cells; Odds Ratio; Genetic Linkage; Neuropeptide Y; gamma-Aminobutyric Acid; Cell Line; Eating; Obesity; Promoter Regions, Genetic; Autoantibodies; Isoenzymes; Feeding Behavior; Genotype; Chromosome Mapping; Glutamate Decarboxylase; Paraventricular Hypothalamic Nucleus; Insulin; Plasmids; Alleles; Aged; Polymorphism, Single Nucleotide; Chromosomes, Human, Pair 10
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.0000068

The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11-12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of gamma-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 [0.681-0.972], p = 0.0049) and an at-risk SNP (-243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053-1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (chi(2) = 7.637, p = 0.02). In the murine insulinoma cell line betaTC3, 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 beta cells, we analyzed GAD65 antibody level as a marker of beta-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 beta-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.