A 2-base pair deletion polymorphism in the partial duplication of the α7 nicotinic acetylcholine gene (CHRFAM7A) on chromosome 15q14 is associated with schizophrenia

Abstract

Multiple genetic linkage studies support the hypothesis that the 15q13-14 chromosomal region contributes to the etiology of schizophrenia. Among the putative candidate genes in this area are the α7 nicotinic acetylcholine receptor gene (CHRNA7) and its partial duplication, CHRFAM7A. A large chromosomal segment including the CHRFAM7A gene locus, but not the CHRNA7 locus, is deleted in some individuals. The CHRFAM7A gene contains a polymorphism consisting of a 2 base pair (2 bp) deletion at position 497-498 bp of exon 6. We employed PCR-based methods to quantify the copy number of CHRFAM7A and the presence of the 2 bp polymorphism in a large, multi-ethnic population. The 2 bp polymorphism was associated with schizophrenia in African Americans (genotype p=0.005, allele p=0.015), and in Caucasians (genotype p=0.015, allele p=0.009). We conclude that the presence of the 2 bp polymorphism at the CHRFAM7A locus may have a functional significance in schizophrenia.

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.…”

“…63,64 Although our cohort were all white Caucasians, some genetic heterogeneity within this ethnic group would not be surprising. Investigating the sample with a panel of ethnically specific SNPs might clarify this issue, although CHRFAM7A variants investigated here show a wide allele frequency variation between ethnicities, 21 suggesting that stratification effects may be particularly pronounced for these variants. Although population stratification is a plausible explanation for the difference between within-and between-family tests of association, other factors may be 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.…”

Axonal α7 nicotinic ACh receptors modulate presynaptic NMDA receptor expression and structural plasticity of glutamatergic presynaptic boutons

“…A convergence of recent genetic evidence identifies α7 nAChR as a potential modifier gene for schizophrenia and AD patients (39)(40)(41). Similarly, deleting the α7 nAChR gene leads to impairment of working/episodic-like memory (42) and alters the synaptic development and cognition in AD transgenic mice (43,44).…”

Deletions flanked by breakpoints 3 and 4 on 15q13 may contribute to abnormal phenotypes

“…Studies have suggested an association between a 2-bp deletion polymorphism of CHRFAM7A, which disrupts the reading frame of the gene, and schizophrenia and dementia. 37,38 However, it is unclear whether this gene's transcript is translated, and homozygous deletions of CHRFAM7A have been found in normal individuals. 39 Therefore, a deletion of this gene may not always cause an abnormal phenotype; however, as suggested by the association between psychosis and lower CHRFAM7A copy number, a deletion of the gene could predispose to neurocognitive disorders.…”