Psychiatric Genetics 00:1᎐4
P.G. Sanda, C. Godaua, P. Riederera, C. Petersb, P. Frankec, M.M. Nothend J. Fritzee, W. Maierc, P. Proppingd, K.-P. Lescha, O. Riessb, T. Sanderf, H. Beckmannaand J. Deckerta,g a Department of Psychiatry, University of Wurzburg, Germany; bDepartment of Medical Genetics, University of Rostock, Germany; cDepartment of Psychiatry, and dDepartment of Human Genetics, University ofBonn, Germany; eDepartment of Psychiatry, University of Frankfurt, Germany; fDepartment of Neurology,Humboldt University of Berlin, Germany; g Department of Psychiatry, University of Munster, Correspondence to Philipp G. Sand, M.D., Clinical Neurochemistry, Department of Psychiatry, University ofWurzburg, Germany. E-mail: [email protected] Received 22 September 2000; accepted 8 January 2000 The enhancement of GABAergic neurotransmission has been closely linked to antipanic drug efficacy. This is the first
study to investigate a putative association of exonic sequence variants of the human GABA

receptor 1 (GABA
and susceptibility to panic disorder. Three DNA sequence variants in exons 1a1, 7 and 11 were assessed by polymerase
chain reaction-based restriction fragment length polymorphism in a case–control study among patients with panic
disorder with and without agoraphobia (DSM III-R

criteria and blood donors. There was no indication of an increased
vulnerability to panic disorder or agoraphobia with respect to the allelic variants under study. Psychiatr Genet 00:1–4
2001 Lippincott Williams & Wilkins.
Keywords: GABA R1, panic disorder, association study
clofen on the release of cholecystokinin-like im-munoreactivity in the human brain ŽRaiteri et al., Panic disorder is characterized by attacks of extreme 1996 , which in turn has been implicated in the anxiety accompanied by sympathetic arousal during experimental induction of stress and panic attacks.
which patients feel an urge to flee or find help. In the general population, lifetime prevalence rates coupled receptor family and are present in all major range from 1 to 3% ŽEaton et al., structures of the human brain on presynaptic termi- evidence for a genetic predisposition to the disorder nals and postsynaptic neurones. Activation of the as shown in both family and twin studies ŽKendler etal., 1993; Maier et al., presynaptic Žauto-.receptor suppresses the release of GABA-mimetic agents in panic disorder has sug- the neurotransmitter ␥-aminobutyric acid Ž gested that symptoms may relate to a dysfunction of supposedly by inhibiting Ca2q influx, whereas the postsynaptic receptor produces prolonged neuronal 1996 . However, studies addressing the role of hyperpolarization by an increase in Kq conductance.
receptors are unique in that they are the have provided negative results ŽSchmidt et al., 1993; only metabotropic receptors known to operate as heterodimers, forming complexes of two closely re- To judge by animal studies ŽQuintero et al., 1985; lated transmembrane proteins, GABA R1 and GABA R2 ŽKaupmann et al., 1998; White et al., ceptors also participate in the modulation of anxiety The gene encoding the human GABA R1 recep- states and could represent targets for novel anxio- tor protein has recently been cloned and mapped to lytic agents ŽKuner et al., 1999; Wickelgren, the chromosomal segment 6p21.3 ŽKaupmann et al., This view is supported by findings on the inhibitory 1997 . Following the elucidation of its genomic orga- nization, three exonic polymorphisms, two of which 0955-8829 ᮊ 2001 Lippincott Williams & Wilkins cause amino acid subsitutions, have been described of German descent, 60 of whom presented with additional agoraphobia ŽSteinlein et al., dressed the putative involvement of these variants in disorder and agoraphobia were diagnosed according the pathogenesis of epilepsy ŽSander et al., to DSMIII-R criteria by means of a structured clini- and of alcohol dependence ŽSander et al., cal interview Ž n s40 probands with SADS-LA, ns While no association was detected with idiopathic epilepsy, mild phenotypic effects were reported for records. The final consensus diagnosis was made by two sequence variants in alcoholism. A twofold in- an experienced psychiatrist prior to genotyping. Only crease in risk for alcohol dependence has been patients with primary and predominant panic dis- observed in the presence of panic disorder ŽKessler order were included in the study. The sex-matched et al., 1997; Schuckit et al., control sample consisted of 89 unrelated blood disruption of late inhibitory postsynaptic potentials donors of German descent Ž31 male, 58 female. All patients had given their informed consent.
pathologies. The anxiolytic effect of the GABA Genomic DNA was extracted from ethylenedi- receptor agonist baclofen in the experimental setting amine tetraacetic acid-blood according to standard of alcohol withdrawal ŽFile et al., procedures. The three exonic polymorphisms of the favour of this hypothesis. In the present study, we GABA R1 gene were then assessed in a polymerase screened a population of patients with panic dis- order and a control population of blood donors for length polymorphism assay. PCR conditions, primer pairs for the three sequence variants, the nucleotide gene sequence variants with panic disorder.
exchange and the resulting substitution of aminoacids, as well as the respective endonuclease for the polymorphic sites, were as described previouslyŽPeters et al., The screening sample included 87 inpatients and was digested by the respective endonuclease using 5 outpatients Ž30 male, 57 female. with panic disorder Ursample and digestion products resolved on Ž TABLE 1. Allele and genotype frequencies of exonic GABA R1 variants OR, Odds ratios; CI, confidence interval.
a Subgroup of patients with panic disorder.
U Type-I error rates for comparisons of allele frequencies (controls versus patients with panic disorder; controls versus patients with panic disorder and additional ies in animals have shown that chronic fluoxetine gels. Bands were visualized by ethidium bromide and administration, a therapeutic option in panic dis- Allele and genotype frequencies, ␹ 2 tests, odds cortex and selectively alters GABA -mediated re- ratios for carriers of a particular allele together with sponses in the hippocampus ŽBeck et al., their 95% confidence interval, and the test for These observations warrant supplementary investi- Hardy᎐Weinberg equilibrium were calculated using gations of regulatory regions of the GABA R1 gene in panic disorder. A number of striking structural two-tailed type I error rate of 5% was chosen as the significance level. Power simulations were conducted been revealed; for example, the interplay of GABA R1 and GABA R2 is just beginning to be dation of the receptor’s heteromer structure servesas an incentive to search for and to study polymor- The allele and genotype frequencies of the three phisms in the GABA R2 gene, located on chromo- exonic GABA R1 variants in the control group, the some 9q22.1, in future association analyses.
group of 87 patients with panic disorder and thesubgroup of 60 patients with additional agoraphobia are presented in Table 1. None of the observed This work was supported by the Deutsche Forschungs- genotype frequencies deviated significantly from gemeinschaft ŽBe 602r8-1, Sa 434r2-2, Ep 7r8-1, De those expected according to the Hardy᎐Weinberg panic sample did not differ significantly from those observed in the control sample Ala20Val, ␹ s0.312, degrees of freedom Ždf. s 1, P s 0.58; Beck SG, Birnstiel S, Choi KC, Pouloit WA Ž etine selectively alters 5-hydroxytryptamine1A and Gly489Ser, ␹ 2 s0.980, dfs1, Ps0.32; T1974C, ␹ 2 gamma-aminobutyric acid B receptor-mediated hyper- polarization in area CA1, but not area CA3, hippocam- ences between controls and the subgroup of patients pal pyramidal cells. J Pharmacol Exp Ther 281:115᎐122.
with panic disorder and agoraphobia did not reach Breslow MF, Fankhauser MP, Potter RL, Meredith KE, significance Ala20Val, ␹ s0.196, dfs1, Ps0.66; Gly489Ser, ␹ 2 s0.676, dfs1, Ps0.41; T1974C, ␹ 2 146:353᎐356.
Budowle B, Chakraborty R, Giusti AM, Eisenberg AJ, on the entire samples of panic patients and controls 1991 . Analysis of the VNTR locus D1S80 by the PCR followed by high-resolution PAGE. Am J indicated that we should expect a statistical power Hum Genet 48:137᎐144.
of )80% to detect a susceptibility factor with a Crowe RR, Wang Z, Noyes R, Albrecht BE, Darlison MG, genotypic relative risk of )3.45 for the Ala20Val polymorphism, and of )2.39 for the T1974C poly- GABA A receptor subunits in panic disorder. Am J
morphism. For the Gly489Ser polymorphism, how- ever, the power of the study was considered insuffi- size calculations: a review and computer program. Con- cient Ža relative risk of G9.45 would be necessary to trol Clin Trials 11:116᎐128.
Eaton WW, Kessler RC, Wittchen HU, Magee WJ Ž Panic and panic disorder in the United States. Arch our findings do not support the assumption that Gen Psychiatry 40:1065᎐1069.
either of the variants confers a major phenotypic effect to the pathogenesis of panic disorder or of nitrendipine, chlordiazepoxide, flumazenil and baclofenon the increased anxiety resulting from alcohol with- drawal. Prog Neuro-Psychopharmacol Biol Psychiatry These results do not necessarily exclude a 16:87᎐93.
pathogenetic influence of the GABA R1 gene in 1990 . The supraspinal anxiolytic effect of the anxiety disorders investigated. In particular, mi- baclofen for spasticity reduction. Am J Phys Med Re-
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nor effects relating to rare sequence variants may have been missed due to sample size and power of anxiety. Depress Anxiety 4:100᎐110.
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