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GAD2 on chromosome 10p12 is a candidate gene for human obesity

Boutin, Philippe, Dina, Christian, Vasseur, Francis, Dubois, Severine, Corset, Laetitia, Seron, Karen, Bekris, Lynn, Cabellon, Janice, Neve, Bernadette, Vasseur-delannoy, Valerie, Chikri, Mohamed, Charles, M. Aline, Clement, Karine, Lernmark, Ake and Froguel, Philippe 2003, GAD2 on chromosome 10p12 is a candidate gene for human obesity, PLOS biology, vol. 1, no. 3, pp. 361-371, doi: 10.1371/journal.pbio.0000068.

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Title GAD2 on chromosome 10p12 is a candidate gene for human obesity
Author(s) Boutin, Philippe
Dina, Christian
Vasseur, Francis
Dubois, Severine
Corset, Laetitia
Seron, Karen
Bekris, Lynn
Cabellon, Janice
Neve, Bernadette
Vasseur-delannoy, Valerie
Chikri, Mohamed
Charles, M. Aline
Clement, Karine
Lernmark, Ake
Froguel, Philippe
Journal name PLOS biology
Volume number 1
Issue number 3
Start page 361
End page 371
Publisher Public Library of Science
Place of publication San Francisco, Calif.
Publication date 2003
ISSN 1544-9173
Summary 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 γ-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 (χ2 = 7.637, p = 0.02). In the murine insulinoma cell line βTC3, 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 β cells, we analyzed GAD65 antibody level as a marker of β-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 β-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.
Language eng
DOI 10.1371/journal.pbio.0000068
Field of Research 060412 Quantitative Genetics (incl Disease and Trait Mapping Genetics)
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2003, Boutin et al.
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Document type: Journal Article
Collection: School of Exercise and Nutrition Sciences
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