Lack of Support for the Association between GAD2 Polymorphisms and Severe Human Obesity

Philipps University of Marburg, Marburg, Hesse, Germany
PLoS Biology (Impact Factor: 9.34). 10/2005; 3(9):e315. DOI: 10.1371/journal.pbio.0030315
Source: PubMed


The demonstration of association between common genetic variants and chronic human diseases such as obesity could have profound implications for the prediction, prevention, and treatment of these conditions. Unequivocal proof of such an association, however, requires independent replication of initial positive findings. Recently, three (-243 A>G, +61450 C>A, and +83897 T>A) single nucleotide polymorphisms (SNPs) within glutamate decarboxylase 2 (GAD2) were found to be associated with class III obesity (body mass index > 40 kg/m2). The association was observed among 188 families (612 individuals) segregating the condition, and a case-control study of 575 cases and 646 lean controls. Functional data supporting a pathophysiological role for one of the SNPs (-243 A>G) were also presented. The gene GAD2 encodes the 65-kDa subunit of glutamic acid decarboxylase-GAD65. In the present study, we attempted to replicate this association in larger groups of individuals, and to extend the functional studies of the -243 A>G SNP. Among 2,359 individuals comprising 693 German nuclear families with severe, early-onset obesity, we found no evidence for a relationship between the three GAD2 SNPs and obesity, whether SNPs were studied individually or as haplotypes. In two independent case-control studies (a total of 680 class III obesity cases and 1,186 lean controls), there was no significant relationship between the -243 A>G SNP and obesity (OR = 0.99, 95% CI 0.83-1.18, p = 0.89) in the pooled sample. These negative findings were recapitulated in a meta-analysis, incorporating all published data for the association between the -243G allele and class III obesity, which yielded an OR of 1.11 (95% CI 0.90-1.36, p = 0.28) in a total sample of 1,252 class III obese cases and 1,800 lean controls. Moreover, analysis of common haplotypes encompassing the GAD2 locus revealed no association with severe obesity in families with the condition. We also obtained functional data for the -243 A>G SNP that does not support a pathophysiological role for this variant in obesity. Potential confounding variables in association studies involving common variants and complex diseases (low power to detect modest genetic effects, overinterpretation of marginal data, population stratification, and biological plausibility) are also discussed in the context of GAD2 and severe obesity.

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Available from: Michael M Swarbrick
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    • "The highest linkage peak provided evidence for the presence of a susceptibility locus for BN on chromosome 10p [126]. Interestingly, this region already showed up in full and partial genome scans for obesity [54, 88, 127, 128]; attempts to identify the underlying gene variant(s) have however not led to clear-cut results [129, 130]. Nevertheless, a gene on chromosome 10p might well be involved in both obesity and BN. "
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    • "Indeed, the G-allele for c. − 243A > G has been associated with a modest reduction of BMI (p = 0.01), as well as lower fasting plasma glucose levels (p = 0.008) and lower 30-min oral glucose tolerance test (OGTT)-related plasma glucose levels (p = 0.04), in a population of 5857 middle-aged, unrelated Danish subjects (mean BMI of 26.3 ± 4.6 kg/m 2 ) [14]. Additionally, Swarbrick et al., who investigated the importance of GAD2 in two large case–control studies and a smaller study of German pedigrees, found no statistical evidence supporting a role of GAD2 for severe obesity [15]. Based on these observations, we investigated whether GAD2 gene sequence variations influence eating behavior traits, energy and macronutrients intake, as well as adiposity in a cohort from the Quebec Family Study. "
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    ABSTRACT: The glutamate decarboxylase 2 (GAD2) gene encodes for the glutamic acid decarboxylase enzyme (GAD65), which is implicated in the formation of the gamma-aminobutyric acid (GABA), a neurotransmitter involved in the regulation of food intake. The objective of the present study was to test for association between GAD2 single-nucleotide polymorphisms (SNPs) and eating behaviors, dietary intake and obesity in subjects (n=873) from the Quebec Family Study (QFS). Energy and macronutrient intakes were measured using a 3-day dietary record and eating behaviors were assessed using the Three-Factor Eating Questionnaire (TFEQ). Six SNPs capturing about 90% of GAD2 gene variability were genotyped and tested for association with age- and BMI- adjusted phenotypes. No evidence of association was found in men. In women, a SNP (rs992990; c.61450 C>A) was associated with disinhibition (p=0.028), emotional susceptibility to disinhibition (p=0.0005) and susceptibility to hunger (p=0.028). Another SNP (rs7908975; c.8473A>C) was associated with carbohydrate (p=0.021) and lipid (p=0.021) intakes, disinhibition (p=0.011) and two of its subscales (emotional and situational susceptibility) as well as with avoidance of fattening foods (p=0.036). Six-year weight gain was two times higher in women carrying the variants associated with eating behaviors: 4.2kg (vs 2.1kg in non-carriers) in A-allele carriers of c.61450 C>A (p=0.038) and 4.9kg (vs 2.5kg in non-carriers) in C-allele carriers of c. 8473 A>C (p=0.013). The results suggest a role for the GAD2 gene in determining food intake, eating behaviors and weight gain over time in women.
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    • "From twin studies it is estimated that up to 80% of the variance in body mass index (BMI) might be genetically determined [1-4]. These genetic contributions seem to be especially important in individuals with severe or early-onset forms of obesity [5]. The molecular mechanisms of obesity are still far from being well understood. "
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