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Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism

Molecular Psychiatry volume 11, pages 752–762 (2006)Cite this article

A Corrigendum to this article was published on 26 July 2006

Abstract

Abnormalities in the gamma-aminobutyric acid (GABA) neurotransmitter system have been noted in subjects with mood and anxiety disorders. Glutamic acid decarboxylase (GAD) enzymes synthesize GABA from glutamate, and, thus, are reasonable candidate susceptibility genes for these conditions. In this study, we examined the GAD1 and GAD2 genes for their association with genetic risk across a range of internalizing disorders. We used multivariate structural equation modeling to identify common genetic risk factors for major depression, generalized anxiety disorder, panic disorder, agoraphobia, social phobia and neuroticism (N) in a sample of 9270 adult subjects from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. One member from each twin pair for whom DNA was available was selected as a case or control based on scoring at the extremes of the genetic factor extracted from the analysis. The resulting sample of 589 cases and 539 controls was entered into a two-stage association study in which candidate loci were screened in stage 1, the positive results of which were tested for replication in stage 2. Several of the six single-nucleotide polymorphisms tested in the GAD1 region demonstrated significant association in both stages, and a combined analysis in all 1128 subjects indicated that they formed a common high-risk haplotype that was significantly over-represented in cases (P=0.003) with effect size OR=1.23. Out of 14 GAD2 markers screened in stage 1, only one met the threshold criteria for follow-up in stage 2. This marker, plus three others that formed significant haplotype combinations in stage 1, did not replicate their association with the phenotype in stage 2. Subject to confirmation in an independent sample, our study suggests that variations in the GAD1 gene may contribute to individual differences in N and impact susceptibility across a range of anxiety disorders and major depression.

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Acknowledgements

This work was supported by NIH grants MH-40828, MH-65322, MH-20030, DA-11287, MH/AA/DA-49492 to KSK and K08 MH-66277-1, as well as a Junior Faculty Research Award from the Anxiety Disorders Association of America, an NARSAD Young Investigator Award and a Pfizer/SWHR Scholars Award to JMH. We acknowledge the contribution of the Virginia Twin Registry, now part of the Mid-Atlantic Twin Registry (MATR), to ascertainment of subjects for this study. The MATR, directed by Drs J Silberg and L Eaves, has received support from the National Institutes of Health, the Carman Trust and the WM Keck, John Templeton and Robert Wood Johnson Foundations.

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  1. Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    J M Hettema, S S An, M C Neale, J Bukszar, E J C G van den Oord, K S Kendler & X Chen

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  1. J M Hettema
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  2. S S An
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  3. M C Neale
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Correspondence to J M Hettema.

Additional information

Preliminary results from this study were presented at the XIIIth World Congress on Psychiatric Genetics, October 14–18, 2005 in Boston, MA, USA.

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Hettema, J., An, S., Neale, M. et al. Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism. Mol Psychiatry 11, 752–762 (2006). https://doi.org/10.1038/sj.mp.4001845

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Keywords

  • glutamic acid decarboxylase
  • depression
  • anxiety
  • neuroticism
  • association study
  • genetics

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