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

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. Access through your institution Buy or subscribe This is a preview of

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MAJOR PSYCHIATRIC AND SUBSTANCE USE DISORDERS AS AN INDEX OF GENETIC RISK AND GENETIC HETEROGENEITY Article Open access 02 September 2024 PHENOTYPIC AND GENETIC MARKERS OF PSYCHOPATHOLOGY IN

A POPULATION-BASED SAMPLE OF OLDER ADULTS Article Open access 24 April 2021 FAMILIAL CO-AGGREGATION AND SHARED HERITABILITY BETWEEN DEPRESSION, ANXIETY, OBESITY AND SUBSTANCE USE Article

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initiation and progression to nicotine dependence. _Am J Med Genet_ 2001; 105: 259–265. Article  CAS  PubMed  Google Scholar  Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * 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 Authors * J M Hettema View author publications You can

also search for this author inPubMed Google Scholar * S S An View author publications You can also search for this author inPubMed Google Scholar * M C Neale View author publications You can

also search for this author inPubMed Google Scholar * J Bukszar View author publications You can also search for this author inPubMed Google Scholar * E J C G van den Oord View author

publications You can also search for this author inPubMed Google Scholar * K S Kendler View author publications You can also search for this author inPubMed Google Scholar * X Chen View

author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR 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) SUPPLEMENTARY INFORMATION SUPPLEMENTARY TABLE 1 (DOC 40 KB) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 21 November 2005 * Revised: 18 April 2006 * Accepted: 28 April 2006 * Published: 23 May 2006 * Issue Date: 01 August 2006

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currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * glutamic acid decarboxylase * depression * anxiety *

neuroticism * association study * genetics