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

Abstract

There is considerable evidence implicating the 15q13.3 region in neuropsychiatric disorders, with the a7 nicotinic receptor gene CHRNA7 the most plausible candidate. This region has multiple duplications and many copy number variants (CNVs). A common CNV involves a partial duplication of CHRNA7 (CHRFAM7A), which occurs in either orientation. We examined the distribution of these alternative genomic arrangements in a large cohort of psychiatric patients, their relatives and controls using the 2-bp deletion polymorphism as a marker for the orientation of CHRFAM7A. We investigated three common alleles for association with psychosis and with the P50 sensory gating deficit, which is strongly associated with psychosis and strongly linked to 15q13.3. We found significant within-family association with P50 (empirical P ¼ 0.004), which is robust to population stratification. Most of the effect came from the 2-bp deletion allele, which tags the variant of CHRFAM7A in the same orientation as CHRNA7. This allele is associated with the presence of the P50 sensory gating deficit (empirical P ¼ 0.0006). Tests comparing within-family and between-family components of association suggest considerable population stratification in the sample. We found no evidence for association with psychosis, but this may reflect lower power using this phenotype. Four out of six previous association studies found association of different psychiatric phenotypes with the same 2-bp deletion allele.

Association Study of the 2-bp Deletion Polymorphism in Exon 6 of theCHRFAM7AGene with Idiopathic Generalized Epilepsy

“…A French group reported an association between the 2-bp deletion and abnormal P50 auditory evoked potentials (Raux et al, 2002), but failed to find an association between the 2-bp deletion and schizophrenia. Such a pattern that showed a strong linkage of this polymorphism to the P50 endophenotype, but only a weak linkage to schizophrenia within the same study, has been recently described by Flomen et al (2013). These results, along with an association of the 2-bp deletion with poor episodic memory (Dempster et al, 2006), indicate the possibility that the CHRFAM7A inversion is connected to some endophenotypes of schizophrenia.…”

“…According to Raux et al (2002) and supported by a recent study by Flomen et al (2013), the 2-bp deletion polymorphism is a risk factor for auditory sensory gating deficit, which characterizes the majority of patients with chronic schizophrenia. As has been noted by Flomen et al (2008), association with the 2-bp deletion of schizophrenia endophenotypes might be due to the orientation of the duplicon containing CHRFAM7A.…”

The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function

“…This allele, CHRFAM7AΔ2bp , is present much more frequently in Caucasian individuals (42%) than in African Americans (14%) and is significantly associated with schizophrenia (Sinkus et al, 2009). The 2bp deletion is associated with the P50 deficit (Flomen et al, 2013; Raux et al, 2002), with poor episodic memory (Dempster et al, 2006), and is inversely associated with idiopathic generalized epilepsy (Rozycka et al, 2013). The 2bp deletion in CHRFAM7A is found less frequently in individuals with a CHRNA7 promoter mutation, and is in linkage disequilibrium with a 3bp intronic insertion in CHRNA7 exon 7, -11insGTT, the latter of which might lead to alternative splicing (Gault et al, 2003; Rozycka et al, 2013).…”

“…Although the 2bp deletion is more common in Caucasians, association to schizophrenia is found in both African Americans and Caucasians (Sinkus et al, 2009). It is also a risk factor for having a P50 sensory processing deficit (Flomen et al, 2013; Raux et al, 2002) and poor episodic memory (Dempster et al, 2006). It seems to be protective for some forms of epilepsy (Rozycka et al, 2013).…”

Ordered Subset Analysis of Copy Number Variation Association with Age at Onset of Alzheimer's Disease

“…We confirmed the CNV calls with TaqMan assay and demonstrated that the deletion allele frequency is 18.85%. Locus specific association studies in schizophrenia and bipolar disorder reported similar allele frequencies [25–27]. …”