The −2 bp deletion in exon 6 of the ‘alpha 7-like’ nicotinic receptor subunit gene is a risk factor for the P50 sensory gating deficit

Abstract

Abnormality in the P50 auditory-evoked potential gating is an endophenotype associated with schizophrenia. Biochemical and genetic studies have suggested that the alpha 7 nicotinic acetylcholine receptor (nAChR) is involved in this sensory gating deficit. Two related alpha 7 genes (CHRNA7 and CHRNA7-like gene) resulting from a partial duplication (from exon 5 to exon 10) are present in the human genome. Two types of genetic variation, a large deletion and a −2 base-pair deletion in exon 6 resulting in a truncation of the open reading frame, affect specifically the CHRNA7-like gene. We developed a simple multiplex PCR assay on genomic DNA, allowing the quantification of the number of exons 6 and the distinction of all possible exon 6 genotypes. Genotyping of 70 schizophrenic patients and 77 controls showed that carrying at least one −2 bp deletion of exon 6 did not constitute a risk factor for schizophrenia. In contrast, the distribution of genotypes differed significantly between subjects with normal and abnormal P50 ratios, with an over-representation of genotypes carrying at least one −2 bp deletion of exon 6 among subjects exhibiting an abnormal P50 ratio. We thus conclude that the −2 bp deletion within the CHRNA7-like gene is a risk factor for P50 sensory gating deficit. Interestingly, most of the effect came from the non schizophrenic group, which may suggest that in schizophrenic patients other risk factors account for the large proportion of subjects exhibiting an abnormal P50 ratio.

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

“…Of the six previous studies involving CHRFAM7A variants and either a psychosis phenotype or endophenotype, 19,[21][22][23][24]67 four found a significant association with the 2-bp deletion. However, there is no consistency with the phenotype involved.…”

“…We found no association of the 2-bp deletion with schizophrenia in the above study, but an association with schizophrenia has since been reported. 21 Other studies have found that the 2-bp deletion is associated with bipolar disorder, 22 P50 sensory gating deficit 23 and deficits in episodic memory, 24 another endophenotype proposed for schizophrenia. Recent genome-wide scans for CNVs showed that much rarer CNVs at 15q13.3, usually involving deletion of B2 Mb from CHRFAM7A to CHRNA7, are overrepresented in many neurological and psychiatric disorders.…”

The promoter −194 C polymorphism of the nicotinic alpha 7 receptor gene has a protective effect against the P50 sensory gating deficit

“…Electroencephalographic activity was recorded as described previously, 5,11 and according to the P50 suppression paradigm. 12,13.…”

“…4 In a previous work, we have shown that the presence of at least one À2 bp deletion located in exon 6 of the CHRNA7-like gene is a risk factor for P50 abnormality in the general population. 5 Recently, Leonard et al 6 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 functional promoter variants in subjects who had an inhibitory deficit.…”

Schizophrenia: an example of complex genetic disease

“…Smoking affects sensory gating. Several studies have shown that promoter variants (in the a7 gene) or variants located in the a7-like gene are associated with P50 inhibition deficits (Raux et al 2002; for review, see Leonard and Freedman 2006). This paradigm has also been used to identify a potential susceptibility locus for schizophrenia on chromosome 15, a region where the gene for the a7 nicotinic receptor is located.…”