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
ᮊ 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
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
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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 Psychiatry 154:1097᎐1100.
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
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pathogenetic influence of the GABA R1 gene in
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‘Materials and methods’ Define SADS-LA and CIDI.
The Top 10 Adult Emergency Medicine Articles from 2007 Bruce A. Macleod, MD, FACEP Michael A. Turturro, MD, FACEP A Randomized Controlled Trial of Multi-Slice Coronary Computed Tomography for Evaluation of Acute Chest Pain. Goldstein JA, Gallagher MJ, O’Neill WW, et al. J Am Coll Cardiol 2007;49:863-871 OBJECTIVES : This study sought to compare the safety, diagnostic ef
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