title: Lack of support for the association between GAD2 polymorphisms and severe human obesity.
abstract: 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.
authors.affiliation: Diabetes Center, University of California, San Francisco, California, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Swarbrick
authors.forename: Björn
authors.initials: B
authors.lastname: Waldenmaier
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.forename: Denise L
authors.initials: DL
authors.lastname: Lind
authors.forename: Martha M
authors.initials: MM
authors.lastname: Cavazos
authors.forename: Frank
authors.initials: F
authors.lastname: Geller
authors.forename: Raphael
authors.initials: R
authors.lastname: Merriman
authors.forename: Anna
authors.initials: A
authors.lastname: Ustaszewska
authors.forename: Mary
authors.initials: M
authors.lastname: Malloy
authors.forename: André
authors.initials: A
authors.lastname: Scherag
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Hsueh
authors.forename: Winfried
authors.initials: W
authors.lastname: Rief
authors.forename: Franck
authors.initials: F
authors.lastname: Mauvais-Jarvis
authors.forename: Clive R
authors.initials: CR
authors.lastname: Pullinger
authors.forename: John P
authors.initials: JP
authors.lastname: Kane
authors.forename: Robert
authors.initials: R
authors.lastname: Dent
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: Anke
authors.initials: A
authors.lastname: Hinney
authors.forename: Johannes
authors.initials: J
authors.lastname: Hebebrand
authors.forename: Christian
authors.initials: C
authors.lastname: Vaisse
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009679:Nuclear Family; D009767:Obesity, Morbid / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length
chemical_list: D005819:Genetic Markers; D007527:Isoenzymes; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2