The promoter -194 C polymorphism of the nicotinic alpha 7 receptor gene has a protective effect against the P50 sensory gating deficit.
ABSTRACT As suggested by several studies, abnormal sensory gating measured by the P50 paradigm could be an endophenotype predisposing to schizophrenia. In a previous work, we have shown a significant association between the presence of at least one -2 bp deletion located within exon 6 of the CHRNA7-like gene and the P50 abnormality in the general population. A recent study involved polymorphisms located in the core promoter region of the CHRNA7 gene as risk factors for the P50 inhibitory deficit. Screening for promoter variants in a large population of schizophrenic patients (n=111) and control subjects (85), for whom auditory-evoked potentials had been recorded did not allow us to replicate these results. By contrast, we showed a significant association between the -194 C allele and a T/C ratio <0.45, thus demonstrating a protective effect of this variant for the sensory gating deficit. Such conflicting results can be reconciled if we consider that the -194 C polymorphism has no causative effect, but is in linkage disequilibrium with other causal variations for the P50 sensory gating deficit, and that different alleles are in disequilibrium in different populations.
- SourceAvailable from: Florence Thibaut
Article: Onde P50 dans la schizophrénie[Show abstract] [Hide abstract]
ABSTRACT: Certains troubles cognitifs présentés par les patients schizophrènes sont interprétables en termes de dysfonctionnement du traitement de l'information au sein de réseaux neuronaux. À cette même échelle neuronale, ces troubles sont la conséquence d'anomalies élémentaires neurochimiques ou électrophysiologiques. Plusieurs marqueurs électrophysiologiques ont été largement étudiés à ce titre dans la schizophrénie : l'anomalie de la poursuite oculaire lente, le paradigme des antisaccades, l'onde P300 et enfin le défaut d'inhibition de l'onde P50 des potentiels évoqués auditifs. Ce dernier paradigme présente un intérêt plus particulier car il est actuellement le seul dont les bases neuroanatomiques, neurochimiques et génétiques semblent mieux appréhendées. Ce défaut d'inhibition neuronale pourrait être à l'origine d'un certain nombre de symptômes schizophréniques positifs tels que les hallucinations. Tenter d'approcher la physiopathologie d'une maladie si hétérogène que la schizophrénie par des marqueurs associés élémentaires définis par une cascade biologique simple représente une réelle alternative aux études menées jusque dans les années 1980. Le défaut de filtrage sensoriel mesuré par le paradigme de l'onde P50 des potentiels évoqués auditifs est l'un de ces endophénotypes. Le gène codant pour la sous-unité a-7 du récepteur nicotinique semble impliqué dans ce mécanisme d'inhibition neuronale au niveau de l'hippocampe. Cette anomalie de filtrage semble indépendante du cours évolutif de la maladie, lorsqu'il s'agit de la schizophrénie. Une association significative entre un polymorphisme situé sur le gène CHRNA7-like (issu pour partie d'une duplication du gène CHRNA7 codant la sous-unité a-7 du récepteur nicotinique) et le défaut d'inhibition de l'onde P50 a pu être montrée alors que ce même polymorphisme ne semble pas associé au phénotype « schizophrénie ». Ces résultats montrent à quel point la schizophrénie relève probablement d'interactions complexes entre de nombreux neuromédiateurs.
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ABSTRACT: Background The effects of smoking on cognitive performance have long been studied, with mixed results. P50 sensory gating has been used as endophenotype for studying nicotinic systems genetics, and P50 gating deficits have been reported to be a sensitive biomarker for cognitive impairment in schizophrenia. This study examined the inter-relationship between P50 suppression, cognitive function, and smoking in a healthy Han Chinese population, which has not been reported before. Methods We recruited 82 healthy male subjects, including 48 smokers and 34 non-smokers who were matched for age and education. The authors measured P50 sensory gating and administered the Chinese-language version of the MATRICS Consensus Cognitive battery (MCCB) and Stroop tests. Results The results showed that the smokers scored lower than nonsmokers on the MCCB Brief Visuospatial Memory Test (BVMT) index and the STROOP test. Furthermore, the MCCB total score was negatively associated with number of cigarettes smoked per day in the smoker group. However, P50 sensory gating was not associated with either smoking status or any cognitive performance. Conclusions Our results show that smoking is associated with cognitive impairment, but not with P50 sensory gating.Drug and Alcohol Dependence 10/2014; · 3.28 Impact Factor
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ABSTRACT: Effects of laser shock processing (LSP) on 00Cr12 alloy's mechanical properties at high temperatures were analyzed by investigating the changing of the residual stress and tensile properties. The results showed that the compressive residual stress produced by LSP, which makes the 00Cr12 alloy's yield strength and tensile strength increase, still played an important role in the high temperature tensile test. The tensile fracture showed that the break position and expand direction were changed because of the residual compressive stress existing, and the residual compressive stress was greatly released with the increasing temperature. The results demonstrated that the cycle, stress amplitude and temperature-dependent relaxation of compressive residual stresses were more pronounced than the decrease of near-surface work strengthening.Materials Science and Engineering A 02/2011; 528(4):1949-1953. · 2.41 Impact Factor
ORIGINAL RESEARCH ARTICLE
The promoter ?194 C polymorphism of the nicotinic alpha
7 receptor gene has a protective effect against the P50
sensory gating deficit
E Houy1,2, G Raux1, F Thibaut1,2, A Belmont2, C Demily1,2, G Allio2, S Haouzir2, G Fouldrin2, M Petit1,2,
T Frebourg1, D Campion1,2
1INSERM EMI 9906, IFRMP, Faculte ´ de Me ´decine et de Pharmacie, Rouen, France;2Services Hospitalo Universitaires de
Psychiatrie, CHU C Nicolle et CHSR, Rouen, France
As suggested by several studies, abnormal sensory gating measured by the P50 paradigm
could be an endophenotype predisposing to schizophrenia. In a previous work, we have
shown a significant association between the presence of at least one ?2bp deletion located
within exon 6 of the CHRNA7-like gene and the P50 abnormality in the general population. A
recent study involved polymorphisms located in the core promoter region of the CHRNA7 gene
as risk factors for the P50 inhibitory deficit. Screening for promoter variants in a large
population of schizophrenic patients (n¼111) and control subjects (85), for whom auditory-
evoked potentials had been recorded did not allow us to replicate these results. By contrast,
we showed a significant association between the ?194 C allele and a T/C ratio o0.45, thus
demonstrating a protective effect of this variant for the sensory gating deficit. Such conflicting
results can be reconciled if we consider that the ?194 C polymorphism has no causative effect,
but is in linkage disequilibrium with other causal variations for the P50 sensory gating deficit,
and that different alleles are in disequilibrium in different populations.
Molecular Psychiatry (2004) 9, 320–322. doi:10.1038/sj.mp.4001443
Published online 21 October 2003
Keywords: schizophrenia; genetics; endophenotype; CHRNA7gene; nicotinic receptor; promo-
ter; polymorphism; P50 sensory gating deficit
Several lines of evidence suggest that the deficit in
the inhibition of the P50-evoked response to repeated
auditory stimuli measured by the T/C ratio could be
an inherited trait predisposing to schizophrenia.1
Biochemical and genetic studies suggest that the
alpha 7 nicotinic receptor may function in an
inhibitory neuronal pathway involved in this phe-
The P50 sensory gating deficit was
genetically linked to 15q13–14.3Two related alpha 7
gene (ie CHRNA7 and CHRNA7-like genes) located
1Mb apart and resulting from a partial duplication of
an ancestral gene map in this chromosomal region.4In
a previous work, we have shown that the presence of
at least one ?2bp deletion located in exon 6 of the
CHRNA7-like gene is a risk factor for P50 abnormality
in the general population.5Recently, Leonard et al6
identified several polymorphisms in a core promoter
region of the CHRNA7 gene. They showed that most
of these variations result in a decreased transcription
by using the luciferase reporter gene assay, and they
reported a significantly greater prevalence of func-
tional promoter variants in subjects who had an
In order to replicate these results in a large population
of schizophrenic patients and control subjects, for
whom auditory-evoked potentials had been recorded,
we compared the distribution of the CHRNA7 core
promoter region polymorphisms between 111 schizo-
phrenic patients and 85 control subjects who were
classified according to their P50 T/C ratio value.
As shown in Table 1, 22% of control subjects as
compared with 88% of schizophrenic patients had
abnormal gating defined by a T/C ratio 40.5. Thus,
although some studies using slightly different proce-
dures were unable to replicate previous findings on
abnormal P50 suppression in schizophrenic pa-
tients,7,8this study confirm the basic results of
Freedman et al.1Sequencing of the 231bp upstream
the CHRNA7 translation initiation site revealed three
different polymorphisms, the distribution of which is
shown in Table 2. All variants were found at the
heterozygous state except in one schizophrenic
patient who was homozygous for the ?86T substitu-
tion. Only one control subject had a double variant
(?86 C/T and ?194 G/C).
Received 20 June 2003; revised 09 September 2003; accepted 17
LANGNP1036 INSERM EMI9906, IFRMP, Faculte ´ de Me ´decine
et de Pharmacie, 22bd Gambetta, Rouen 76183, France.
Molecular Psychiatry (2004) 9, 320–322
& 2004 Nature Publishing Group All rights reserved 1359-4184/04 $25.00
In accordance with the data from Leonard et al,6
two variants were found to be more common in the
white population: the subjects carrying the ?194 G/C
polymorphism and the ?86 C/T polymorphism
account for 91% of the subjects carrying at least one
polymorphism. We analysed separately these two
polymorphisms. The distribution of the ?86 C/T
polymorphism did not significantly differ between
subjects with normal and abnormal T/C ratio. In
contrast, we found a significant association (w2¼5.14;
df¼1, Po0.02) between the ?194 C allele and a T/C
ratio o0.45 (Table 3). Thus, the presence of this
polymorphism is protective for the sensory gating
deficit. This finding is clearly inconsistent with the
results of Leonard et al,6who found an association
between the CHRNA7 promoter variants and higher
P50 ratio in control subjects. However, these conflict-
ing results can be reconciled if we consider that the
?194 G/C polymorphism is not causative, but is in
linkage disequilibrium with other causal variations
for the P50 sensory gating deficit, and that different
alleles are in disequilibrium in different populations.
It is interesting to note that the effect of the ?194 C
allele on the transcriptional activity of the CHRNA7
gene is very weak, which argues against a direct role.
Material and methods
Unrelated schizophrenics patients (n¼111) were
included in this study (32 females and 79 males aged
29.477.8 years). Diagnoses were made according to
DSM IV9criteria by two trained psychiatrists after
clinical interviews, using the Schizophrenia Disor-
ders Lifetime Version (SADS-LA10). The control
sample included 45 females and 40 males (aged
36.279.5 years) free of personal and familial history
of neurological or psychiatric disease. Control sub-
whereas all schizophrenic patients received typical
neuroleptic treatments. All subjects were French
Caucasians originating from Normandy. All subjects
gave written informed consent for genetic study and
Electroencephalographic activity was recorded as
described previously,5,11and according to the P50
suppression paradigm.12,13.Auditory stimuli were de-
livered in a conditioning-testing paradigm. Click
pairs (C, conditioning click; T, testing click; 500ms
interclick interval) were delivered with a fixed
interpair interval of 10s. A series of paired clicks
were presented through a set of headphones. The
intensity of the clicks was adjusted to 100db. Evoked
potential signals were collected from electrodes
placed at the vertex. The amplitude of P50 was
defined as the absolute difference between the most
positive peak within the specified range after click
onset and the preceding negative peak. The latency
was measured as the time delay to peak onset after the
stimulus. The gating of the P50 wave was calculated
as the ratio (T/C) of the amplitude of the testing
response (T) to the amplitude of the conditioning
response (C). Subjects with values between 0.45 and
0.50 (three schizophrenic patients) were not included
in the study.
To investigate the core promoter region of the
CHRNA7 gene, we amplified and sequenced this
region using a primer set described by Leonard et al6
and the same PCR conditions: sense primer was
50AGTACCTCCCGCTCACACCTCG30; and antisense
primer was 50ATGTTGAGTCCCGGAGCTGCAG 30;
the size of the amplicon was 271bp. Mutation
screening was performed on an Applied Biosystems
model 377XL automated sequencer (Applied Biosys-
tems, Foster City, CA, USA).
w2tests were used for genotype distribution compar-
isons (using the Yates correction if necessary).
This study was supported by a grant from Pfizer.
Distribution of P50 T/C ratio among 196 subjects
T/C ratio 40.5 (n¼115)
T/C ratio o0.45 (n¼81)
among 196 subjects
Distribution of CHRNA7 promoter polymorphisms
Control subjectsSchizophrenic patients
All polymorphisms are found at the heterozygous state
except for one patient who is homozygous for the ?86 T
G/C variant among 196 subjects with normal and abnormal
P50 ratio regardless of their clinical status
Distribution of the genotypes according to the ?194
T/C ratio 40.5 (n¼115)
T/C ratio o0.45 (n¼81)
w2¼5.14; df¼1; Po0.02.
?194 C polymorphism of the nicotinic alpha 7 receptor gene
E Houy et al
1 Freedman R, Adler LE, Leonard S. Alternative phenotypes for the
complex genetics of schizophrenia. Biol Psychiatry 1999; 45: 551–
2 Leonard S, Adams C, Breese CR, Adler LE, Bickford P, Byerley Wet
al. Nicotinic receptor function in schizophrenia. Schizophrenia
Bull 1996; 22: 431–444.
3 Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A,
Davis A et al. Linkage of a neurophysiological deficit in
schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci
USA 1997; 94: 587–592.
4 Gault J, Robinson M, Berger R, Drebing C, Logel J, Hopkins J et al.
Genomic organization and partial duplication of the human alpha
7 neuronal nicotinic acetylcholine receptor gene (CHRNA7).
Genomics 1998; 52: 173–185.
5 Raux G, Bonnet-Brilhault F, Louchart S, Houy E, Gantier R,
Levillain D et al. The ?2bp deletion in exon 6 of the alpha 7-like
nicotinic receptor subunit gene is a risk factor for the P50 sensory
gating deficit. Mol Psychiatry 2002; 7: 1006–1011.
6 Leonard S, Gault J, Hopkins J, Logel J, Vianzon R, Short M et al.
Association of the promoter variants in the a7 nicotinic acetylcho-
line receptor subunit gene with an inhibitory deficit found in
schizophrenia. Arch Gen Psychiatry 2002; 59: 1085–1096.
7 Kathman N, Engel R. Sensory gating in normals and schizophre-
nics: a failure to find strong P50 suppression in normals. Biol
Psychiatry 1990; 27: 1216–1226.
8 Bramon E, Stagias K, Croft RJ, McDonald C, Muray RM. The P50
waveform is normal in people with schizophrenia and their
relatives. Schizophrenia Res 2002; 53: 214.
9 American Psychiatry Association. Diagnostic and Statistical
Manual of Mental Disorders, 4th edn revised American Psychiatric
Press: Washington, DC, 1994.
10 Fyer AJ, Endicott J, Manuzza S, Klein DF. Schedule for affective
disorders and schizophrenia—lifetime version modified for the
study of anxiety disorders. In: Anxiety Disorders Clinic. Psychia-
tric Institute Press: New York State, NY, 1985.
11 Louchart-de la Chapelle S, Levillain D, Me ´nard JF, Van Der Elst A,
Allio G, Haouzir S et al. P50 inhibitory gating deficit is correlated
with the negative symptomatology of schizophrenia. Psychiatry
Res 2003, (in press).
12 Freedman R, Adler A, Waldo M. Gating of the auditory evoked
potential in children and adults. Psychophysiology 1987; 24: 223–
13 Nagamoto HT, Adler LE, Waldo M, Griffith J, Freedman R. Gating
of auditory response in schizophrenics and normal controls.
Effects of recording site and stimulation interval on the P50 wave.
Schizophrenia Res 1991; 4: 31–40.
?194 C polymorphism of the nicotinic alpha 7 receptor gene
E Houy et al