ArticlePLoS biology2003
GAD2 on chromosome 10p12 is a candidate gene for human obesity.
Article in PLoS biology, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.
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39 citing papers in PubMed, 1 synthesis or guideline pooled it, 152 citations in OpenAlex.
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- Association of the -243A>G, +61450C>A Polymorphisms of the Glutamate Decarboxylase 2 (GAD2) Gene with Obesity and Insulin Level in North Indian Population.Iranian journal of public health · 2016Article
- Genetic variants in AKR1B10 associate with human eating behavior.BMC genetics · 2015Article
- Adaptive human CDKAL1 variants underlie hormonal response variations at the enteroinsular axis.PloS one · 2014Article
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- Molecular characterization of the porcine MTPAP gene associated with meat quality traits: chromosome localization, expression distribution, and transcriptional regulation.Molecular and cellular biochemistry · 2012Article
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- Identification of metabolic modifiers that underlie phenotypic variations in energy-balance regulation.Diabetes · 2011Article
- Fine-mapping of obesity-related quantitative trait loci in an F9/10 advanced intercross line.Obesity (Silver Spring, Md.) · 2010Article
- Eating disorders: the current status of molecular genetic research.European child & adolescent psychiatry · 2010Review
- Metabolic syndrome components in murine models.Endocrine, metabolic & immune disorders drug targets · 2010Review
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- Multivariate association test using haplotype trend regression.Annals of human genetics · 2009Article
- The genetic contribution to non-syndromic human obesity.Nature reviews. Genetics · 2009Review
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15 authors at 5 institutions in 4 countries.
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Abstract
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.
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