Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia.
BACKGROUND
The alpha7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) has been implicated as a candidate gene for schizophrenia, and for an auditory sensory processing deficit found in the disease, by both genetic linkage at 15q14 and biochemical data. The expression of CHRNA7 is reduced in several brain regions in schizophrenic subjects compared with control subjects. This study presents DNA sequence analysis of the core promoter region for CHRNA7 in schizophrenic and control subjects.


METHODS
Single-strand conformation polymorphism analysis and DNA sequencing were used for mutation screening of the core promoter in the CHRNA7 gene. The sample included subjects from 166 schizophrenic families and 165 controls. Controls had no evidence of current or past psychosis and had auditory evoked potentials recorded.


RESULTS
Multiple polymorphic patterns were identified in the CHRNA7 core promoter in both schizophrenic and control subjects. Functional analysis of polymorphisms indicated that transcription was reduced. The prevalence of functional promoter variants was statistically greater in schizophrenic subjects than in the controls. Presence of an alpha7 promoter polymorphism in controls was associated with failure to inhibit the P50 auditory evoked potential response.


CONCLUSIONS
Although linkage disequilibrium with other genetic alterations cannot be excluded, the CHRNA7 core promoter variants, found in this study, may contribute to a common pathophysiologic feature of schizophrenia.
Leonard
Sherry
S
Department of Psychiatry, Campus Box C-268-71, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Denver, CO 80262, USA. Sherry.Leonard@UCHSC.edu
Gault
Judith
J
Hopkins
Jan
J
Logel
Judith
J
Vianzon
Ruby
R
Short
Margaret
M
Drebing
Carla
C
Berger
Ralph
R
Venn
Diana
D
Sirota
Pinkhas
P
Zerbe
Gary
G
Olincy
Ann
A
Ross
Randal G
RG
Adler
Lawrence E
LE
Freedman
Robert
R
D001308:Auditory Perceptual Disorders / Q000235:genetics / Q000473:pathology / Q000523:psychology; D001921:Brain / Q000473:pathology; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15; D004252:DNA Mutational Analysis; D005072:Evoked Potentials, Auditory / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008214:Lymphocytes / Q000473:pathology; D009433:Neural Inhibition / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic; D011978:Receptors, Nicotinic / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D012565:Schizophrenic Psychology; D017422:Sequence Analysis, DNA; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor