Polymorphisms in the GAD2 gene‐region are associated with susceptibility for unipolar depression and with a risk factor for anxiety disorders
Abstract
Glutamate decarboxylase (GAD) is the rate limiting enzyme for conversion of glutamic acid to gamma‐aminobutyric acid (GABA). The GAD 65 kDa isoform is encoded by the gene GAD2 and is mainly expressed in synaptic terminals. It serves as an apoenzyme, which shows enhanced availability in situations of stress, responding to short‐term demands for GABA. We analyzed 18 single nucleotide polymorphisms (SNPs) in the GAD2‐gene region for associations with psychiatric diagnosis and behavioral inhibition (BI) derived from the personality traits neuroticism and extraversion as defined by the Eysenck Personality Questionaire (EPQ). A total of 268 patients with anxiety disorder (AD), 541 with unipolar depression (MD), and 541 healthy controls were included. We observe associations for five tag‐SNPs with BI in the AD‐ and control samples as well as two additional case–control associations in the MD‐sample. The associated SNPs lie within a 16KB linkage disequilibrium‐block, including putative 5′ GAD2‐promoter‐elements as well as the 3′ end of the gene MYO3A. Using open access mRNA‐expression data, we could show that BI‐associated SNPs appear to be associated with differences in MYO3A‐ but not GAD2 lymphoblastoid‐mRNA expression levels. These results support earlier studies that suggest associations of polymorphisms within the GAD2 locus with anxiety and affective disorders. However, data from expression studies imply that these polymorphisms could tag functional effects on the neighboring gene MYO3A, which is also expressed in the brain, including the cingulate cortex and the amygdala. © 2009 Wiley‐Liss, Inc.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A polymorphic variant glutamic acid decarboxylase 2 (GAD2) that is described as an enzyme involved in GABA synthesis and which seems to be severely impaired in ANX disorders may be also involved in DD.
“In this way, it was reported that a polymorphic variant glutamic acid decarboxylase 2 (GAD2) that is described as an enzyme involved in GABA synthesis and which seems to be severely impaired in ANX disorders [236] may be also involved in DD [237].”
From Oxidative Stress Implications in the Affective Disorders: Main Biomarkers, Animal Models Relevance, Genetic Perspectives, and Antioxidant Approaches (2016) · cites this paper as [237]
Cites
An inventory for measuring depression
BECK, A. T. (1961) · Archives of General Psychiatry · doi:10.1001/archpsyc.1961.01710120031004 · Cited by 38,032 · see citing works
Hamilton, M. (1960) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.23.1.56 · Cited by 32,817 · see citing works
Haploview: analysis and visualization of LD and haplotype maps
Barrett, J., Fry, B., Maller, J., & Daly, M. (2005) · Bioinform. · doi:10.1093/bioinformatics/bth457 · Cited by 15,086 · see citing works
Kessler, R. C., Chiu, W. T., Demler, O., & Walters, E. E. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.6.617 · Cited by 12,052 · see citing works
The assessment of anxiety states by rating
HAMILTON, M. (1959) · British Journal of Medical Psychology · doi:10.1111/j.2044-8341.1959.tb00467.x · Cited by 11,455 · see citing works
The International HapMap Project
†The International HapMap Consortium, Genotyping centres: Baylor College of Medicine and ParAllele BioScience, Gibbs, R. A., Belmont, J. W., Hardenbol, P., Willis, T. D., Yu, F., Chinese HapMap Consortium, Yang, H., Ch'ang, L.-Y., et al. (2003) · Nature · doi:10.1038/nature02168 · Cited by 6,057 · see citing works
The Structure of Haplotype Blocks in the Human Genome
Gabriel, S. B., Schaffner, S. F., Nguyen, H., Moore, J. M., Roy, J., Blumenstiel, B., Higgins, J., DeFelice, M., Lochner, A., Faggart, M., et al. (2002) · Science · doi:10.1126/science.1069424 · Cited by 5,863 · see citing works
Genome-wide atlas of gene expression in the adult mouse brain
Lein, E. S., Hawrylycz, M. J., Ao, N., Ayres, M., Bensinger, A., Bernard, A., Boe, A. F., Boguski, M. S., Brockway, K. S., Byrnes, E. J., et al. (2007) · Nature · doi:10.1038/nature05453 · Cited by 5,572 · see citing works
The psychology of fear and stress
(1988) · Choice Reviews Online · doi:10.5860/choice.26-2399 · Cited by 3,134 · see citing works
A Human Protein-Protein Interaction Network: A Resource for Annotating the Proteome
Stelzl, U., Worm, U., Lalowski, M. M., Haenig, C., Brembeck, F. H., Goehler, H., Strödicke, M., Zenkner, M., Schoenherr, A., Koeppen, S., et al. (2005) · Cell · doi:10.1016/j.cell.2005.08.029 · Cited by 2,389 · see citing works
Kessler, R. C. (1997) · Archives of General Psychiatry · doi:10.1001/archpsyc.1997.01830160031005 · Cited by 2,085 · see citing works
The psychophysiological basis of introversion-extraversion
Gray, J. A. (1970) · Behaviour Research and Therapy · doi:10.1016/0005-7967(70)90069-0 · Cited by 1,558 · see citing works
Two genes encode distinct glutamate decarboxylases
Erlander, M. G., Tillakaratne, N. J. K., Feldblum, S., Patel, N., & Tobin, A. J. (1991) · Neuron · doi:10.1016/0896-6273(91)90077-d · Cited by 1,213 · see citing works
Population genomics of human gene expression
Stranger, B. E., Nica, A. C., Forrest, M. S., Dimas, A. S., Bird, C., Beazley, C., Ingle, C., Dunning, M., Flicek, P., Koller, D., et al. (2007) · Nature Genetics · doi:10.1038/ng2142 · Cited by 1,132 · see citing works
A unified biosocial theory of personality and its role in the development of anxiety states.
Cr, C. (1986) · PubMed · Cited by 1,090 · see citing works
Resampling-Based Multiple Testing: Examples and Methods for p-Value Adjustment
Chaubey, Y. P., Westfall, P. H., & Young, S. S. (1993) · Technometrics · doi:10.2307/1270279 · Cited by 943 · see citing works
Kaufman, D. L., Houser, C. R., & Tobin, A. J. (1991) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1991.tb08211.x · Cited by 789 · see citing works
Kushner, M. G. (2000) · Clinical Psychology Review · doi:10.1016/s0272-7358(99)00027-6 · Cited by 782 · see citing works
Further evidence of association between behavioral inhibition and social anxiety in children
Biederman, J., Hirshfeld-Becker, D. R., Rosenbaum, J. F., Hérot, C., Friedman, D., Snidman, N., Kagan, J., & Faraone, S. V. (2001) · American Journal of Psychiatry · doi:10.1176/appi.ajp.158.10.1673 · Cited by 655 · see citing works
Regulation of γ‐Aminobutyric Acid Synthesis in the Brain
Martin, D. L., & Rimvall, K. (1993) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1993.tb03165.x · Cited by 615 · see citing works
The Neuropsychology of Temperament
Gray, J. A. (1991) · Springer eBooks · doi:10.1007/978-1-4899-0643-4_8 · Cited by 551 · see citing works
Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded by a single gene.
Bu, D.-F., Erlander, M. G., Hitz, B. C., Tillakaratne, N. J. K., Kaufman, D. L., Wagner-McPherson, C., Evans, G. A., & Tobin, A. J. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.6.2115 · Cited by 493 · see citing works
A survey of genetic human cortical gene expression
Myers, A. J., Gibbs, J. R., Webster, J. A., Rohrer, K., Zhao, A., Marlowe, L., Kaleem, M., Leung, D., Bryden, L., Nath, P., et al. (2007) · Nature Genetics · doi:10.1038/ng.2007.16 · Cited by 479 · see citing works
Bolton, J. M., Robinson, J. L., & Sareen, J. (2008) · Journal of Affective Disorders · doi:10.1016/j.jad.2008.10.003 · Cited by 453 · see citing works
Prevalence of anxiety disorders and their comorbidity with mood and addictive disorders
Regier, D. A., Rae, D. S., Narrow, W. E., Kaelber, C. T., & Schatzberg, A. F. (1998) · British Journal of Psychiatry · doi:10.1192/s0007125000293483 · Cited by 407 · see citing works
Feldblum, S., Erlander, M. G., & Tobin, A. J. (1993) · Journal of Neuroscience Research · doi:10.1002/jnr.490340612 · Cited by 284 · see citing works
Karlsen, A. E., Hagopian, W., Grubin, C. E., Dube, S., Distèche, C. M., Adler, D. A., Bärmeier, H., Mathewes, S. L., Grant, F. J., & Foster, D. C. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.19.8337 · Cited by 279 · see citing works
Linking Self-Reported Childhood Behavioral Inhibition to Adolescent Social Phobia
HAYWARD, C., Killen, J. D., KRAEMER, H. C., & Taylor, C. B. (1998) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-199812000-00015 · Cited by 279 · see citing works
Bowers, G., Cullinan, W. E., & Herman, J. P. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-15-05938.1998 · Cited by 250 · see citing works
Behavioral Inhibition in Childhood: A Risk Factor for Anxiety Disorders
Rosenbaum, J. F., Biederman, J., Bolduc, E. A., Faraone, S. V., Chaloff, J., HIRSHFELD, D. R., & Kagan, J. (1993) · Harvard Review of Psychiatry · doi:10.3109/10673229309017052 · Cited by 248 · see citing works
Kash, S. F., Tecott, L. H., Hodge, C. W., & Bækkeskov, S. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.4.1698 · Cited by 216 · see citing works
Robinson, J. L., Sareen, J., Cox, B. J., & Bolton, J. M. (2008) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2008.03.013 · Cited by 213 · see citing works
What is the genetic relationship between anxiety and depression?
Hettema, J. M. (2008) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.30171 · Cited by 207 · see citing works
Hennings, J. M., Owashi, T., Binder, E. B., Horstmann, S., Menke, A., Kloiber, S. M., Dose, T., Wollweber, B., Spieler, D., Messer, T., et al. (2008) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2008.05.002 · Cited by 191 · see citing works
Self-citationBienvenu, O. J., Hettema, J. M., Neale, M. C., Prescott, C. A., & Kendler, K. S. (2007) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2007.06101667 · Cited by 186 · see citing works
Hettema, J. M., An, S., Neale, M. C., Bukszár, J., van den Oord, E. J. C. G., Kendler, K. S., & Chen, X. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001845 · Cited by 175 · see citing works
Smoller, J. W., Yamaki, L. H., Fagerness, J. A., Biederman, J., Racette, S., Laird, N. M., Kagan, J., Snidman, N. C., Faraone, S. V., Hirshfeld‐Becker, D. R., et al. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.02.018 · Cited by 168 · see citing works
Wittchen, H. ‐., Höfler, M., Gander, F., Pfister, H., Storz, S., Üstün, B., Müller, N., & Kessler, R. C. (1999) · International Journal of Methods in Psychiatric Research · doi:10.1002/mpr.57 · Cited by 149 · see citing works
Influence of RGS2 on Anxiety-Related Temperament, Personality, and Brain Function
Smoller, J. W., Paulus, M. P., Fagerness, J. A., Purcell, S., Yamaki, L. H., Hirshfeld‐Becker, D. R., Biederman, J., Rosenbaum, J. F., Gelernter, J. E., & Stein, M. B. (2008) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2007.48 · Cited by 148 · see citing works
Orbitofrontal thickness, retention of fear extinction, and extraversion
Rauch, S., Milad, M., Orr, S., Quinn, B., Fischl, B., & Pitman, R. (2005) · NeuroReport · doi:10.1097/01.wnr.0000186599.66243.50 · Cited by 142 · see citing works
Smoller, J. W., Rosenbaum, J. F., Biederman, J., Kennedy, J. C., Dai, D., Racette, S., Laird, N. M., Kagan, J., Snidman, N. C., Hirshfeld‐Becker, D. R., et al. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(03)00598-5 · Cited by 140 · see citing works
Hettema, J. M., An, S., Neale, M. C., Bukszár, J., van den Oord, E. J. C. G., Kendler, K. S., & Chen, X.-X. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001858 · Cited by 137 · see citing works
The nosologic relationship between generalized anxiety disorder and major depression
Hettema, J. M. (2008) · Depression and Anxiety · doi:10.1002/da.20491 · Cited by 119 · see citing works
Ruch, W. (1999) · Zeitschrift für Differentielle und Diagnostische Psychologie · doi:10.1024//0170-1789.20.1.1 · Cited by 113 · see citing works
Karp, S. J., Masu, M., Eki, T., et al. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)53754-6 · Cited by 103 · see citing works
The Relationship of Behavioral Inhibition and Shyness to Anxiety Disorder
Ameringen, M. V., Mancini, C., & Oakman, J. M. (1998) · The Journal of Nervous and Mental Disease · doi:10.1097/00005053-199807000-00007 · Cited by 100 · see citing works
ALCOHOL PROBLEMS AND ANXIETY DISORDERS—A CRITICAL REVIEW
Allan, C. A. (1995) · Alcohol and Alcoholism · doi:10.1093/oxfordjournals.alcalc.a045708 · Cited by 93 · see citing works
Is behavioral inhibition a risk factor for depression?
Gladstone, G. L., & Parker, G. B. (2006) · Journal of Affective Disorders · doi:10.1016/j.jad.2006.04.015 · Cited by 77 · see citing works
Bu, D., & Tobin, A. J. (1994) · Genomics · doi:10.1006/geno.1994.1246 · Cited by 76 · see citing works
Gray's behavioral inhibition system: A psychometric examination
MacAndrew, C., & Steele, T. (1991) · Personality and Individual Differences · doi:10.1016/0191-8869(91)90099-w · Cited by 71 · see citing works
Zhao, X., Li, H., Shi, Y., Tang, R., Chen, W., Liu, J., Feng, G., Shi, J., Yan, L., Liu, H., et al. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.10.023 · Cited by 70 · see citing works
Comorbidity of Mood and Anxiety Disorders: The Rule, Not the Exception?
Nemeroff, C. B. (2002) · American Journal of Psychiatry · doi:10.1176/appi.ajp.159.1.3 · Cited by 68 · see citing works
Altered conditioned fear behavior in glutamate decarboxylase 65 null mutant mice
Stork, O., Yamanaka, H., Stork, S., Kume, N., & Obata, K. (2003) · Genes Brain & Behavior · doi:10.1034/j.1601-183x.2003.00008.x · Cited by 63 · see citing works
Genetic association analysis of behavioral inhibition using candidate loci from mouse models
Smoller, J. W., Rosenbaum, J. F., Biederman, J., Susswein, L. S., Kennedy, J. F., Kagan, J., Snidman, N. C., Laird, N. M., Tsuang, M. T., Faraone, S. V., et al. (2001) · American Journal of Medical Genetics · doi:10.1002/ajmg.1328 · Cited by 59 · see citing works
Gonzales, C., Kaufman, D. L., Tobin, A. J., & Chesselet, M. (1991) · Journal of Neurocytology · doi:10.1007/bf01187913 · Cited by 58 · see citing works
Alcohol abuse, substance abuse, and panic disorder
Cowley, D. S. (1992) · The American Journal of Medicine · doi:10.1016/0002-9343(92)90136-y · Cited by 54 · see citing works
Alcohol Use Disorders and Panic Disorder
Cosci, F., Schruers, K. R. J., Abrams, K. B., & Griez, E. J. L. (2007) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v68n0608 · Cited by 53 · see citing works
Generalised Anxiety Disorder: relationships with Eysenck's, Gray's and Newman's theories
Gomez, R., & Francis, L. M. (2003) · Personality and Individual Differences · doi:10.1016/s0191-8869(02)00020-x · Cited by 45 · see citing works
Georgi, A., Jamra, R. A., Klein, K., et al. (2007) · Psychiatric Genetics · doi:10.1097/ypg.0b013e3280c1e5fb · Cited by 41 · see citing works
Mapping of Glutamic Acid Decarboxylase (GAD) Genes
Edelhoff, S., Grubin, C. E., Karlsen, A. E., et al. (1993) · Genomics · doi:10.1006/geno.1993.1288 · Cited by 32 · see citing works
Plasma glutamate decarboxylase activity in neuropsychiatry
Kaiya, H., Namba, M., Yoshida, H., et al. (1982) · Psychiatry Research · doi:10.1016/0165-1781(82)90023-3 · Cited by 31 · see citing works
Mutation screen of the GAD2 gene and association study of alcoholism in three populations
Lappalainen, J., Krupitsky, E. M., Kranzler, H. R., Luο, X., Remizov, M., Пчелина, С. Н., Taraskina, A., Zvartau, E. E., Räsänen, P. K., Mäkikyrö, T., et al. (2006) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30377 · Cited by 25 · see citing works
Roginski, R. S., Raj, B. K. M., Finkernagel, S. W., et al. (2001) · Cytogenetic and Genome Research · doi:10.1159/000056971 · Cited by 8 · see citing works
Theories of Personality and Performance
Eysenck, H. J., & Eysenck, M. W. (1985) · Personality and Individual Differences · doi:10.1007/978-1-4613-2413-3_7 · Cited by 4 · see citing works
Putting Humpty Dumpty together again: the anxious personality and its inheritance
Gray, J. A., & McNaughton, N. (2003) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780198522713.003.0012 · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Milak, M. S., Proper, C. J., Mulhern, S. T., Parter, A. L., Kegeles, L. S., Ogden, R. T., Mao, X., Rodriguez, C. I., Oquendo, M. A., Suckow, R. F., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.83 · Cited by 144 · see citing works
Rosso, I. M., Weiner, M. R., Crowley, D. J., Silveri, M. M., Rauch, S. L., & Jensen, J. E. (2014) · Depression and Anxiety · doi:10.1002/da.22155 · Cited by 101 · see citing works
Balmus, I. M., Ciobica, A., Antioch, I., Dobrin, R., & Timofte, D. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/3975101 · Cited by 103 · see citing works
“In this way, it was reported that a polymorphic variant glutamic acid decarboxylase 2 (GAD2) that is described as an enzyme involved in GABA synthesis and which seems to be severely impaired in ANX disorders [236] may be also involved in DD [237].”
BackgroundYin, H., Pantazatos, S. P., Galfalvy, H., Huang, Y., Rosoklija, G. B., Dwork, A. J., Burke, A., Arango, V., Oquendo, M. A., & Mann, J. J. (2016) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32423 · Cited by 91 · see citing works
Domschke, K., Tidow, N., Schrempf, M., Schwarte, K., Klauke, B., Reif, A., Kersting, A., Arolt, V., Zwanzger, P., & Deckert, J. (2013) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2013.07.014 · Cited by 87 · see citing works
- Authors
- Unschuld, P. G., Ising, M., Specht, M., Erhardt, A., Ripke, S., Heck, A., Kloiber, S., Straub, V., Brueckl, T., Müller‐Myhsok, B., Holsboer, F., & Binder, E. B.
- Affiliations
- Max Planck Society (DE)
- Corresponding author
- Unschuld, Paul G.
- ORCID
- Venue
- American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
- Publisher
- Wiley
- Published
- 2009-02-19
- Volume
- 150B
- Issue
- 8
- Pages
- 1100-1109
- ISSN
- 1552-4841 (ISSN-L)
- 1552-485X
- OpenAlex
- W2042686214
- Cited by
- 40
- References
- 65
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2018: 6 · 2017: 1 · 2016: 6 · 2015: 5 · 2014: 1 · 2013: 7 · 2012: 1
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- Bundesministerium für Bildung und Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- GAD-2, glutamic acid decarboxylase, GABA synthesis, major depressive disorder, anxiety disorders, single nucleotide polymorphisms, behavioral inhibition, neuroticism, extraversion, linkage disequilibrium, promoter polymorphism, gene expression, genetic susceptibility
- MeSH terms
- Anxiety Disorders, Brain Chemistry, Depressive Disorder, Glutamate Decarboxylase, Humans, Polymorphism, Genetic, Surveys and Questionnaires, Risk Factors, RNA, Messenger, Linkage Disequilibrium, Case-Control Studies, Myosin Heavy Chains, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Myosin Type III
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
