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

The human α7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is ubiquitously expressed in both the central nervous system and in the periphery. CHRNA7 is genetically linked to multiple disorders with cognitive deficits, including schizophrenia, bipolar disorder, ADHD, epilepsy, Alzheimer's disease, and Rett syndrome. The regulation of CHRNA7 is complex; more than a dozen mechanisms are known, one of which is a partial duplication of the parent gene. Exons 5-10 of CHRNA7 on chromosome 15 were duplicated and inserted 1.6 Mb upstream of CHRNA7, interrupting an earlier partial duplication of two other genes. The chimeric CHRFAM7A gene product, dupα7, assembles with α7 subunits, resulting in a dominant negative regulation of function. The duplication is human specific, occurring neither in primates nor in rodents. The duplicated α7 sequence in exons 5-10 of CHRFAM7A is almost identical to CHRNA7, and thus is not completely queried in high throughput genetic studies (GWAS). Further, pre-clinical animal models of the α7nAChR utilized in drug development research do not have CHRFAM7A (dupα7) and cannot fully model human drug responses. The wide expression of CHRNA7, its multiple functions and modes of regulation present challenges for study of this gene in disease. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.

Expression of immune genes on chromosome 6p21.3-22.1 in schizophrenia.

Schizophrenia is a common mental illness with a large genetic component. Three genome-wide association studies have implicated the major histocompatibility complex gene region on chromosome 6p21.3-22.1 in schizophrenia. In addition, nicotine, which is commonly abused in schizophrenia, affects the expression of central nervous system immune genes. Messenger RNA levels for genes in the 6p21.3-22.1 region were measured in human postmortem hippocampus of 89 subjects. The effects of schizophrenia diagnosis, smoking and systemic inflammatory illness were compared. Cell-specific expression patterns for the class I major histocompatibility complex gene HLA-A were explored utilizing in situ hybridization. Expression of five genes was altered in schizophrenic subjects. Messenger RNA levels for the class I major histocompatibility complex antigen HLA-B were increased in schizophrenic nonsmokers, while levels for smokers were indistinguishable from those of controls. ß2 microglobulin, HLA-A and Notch4 were all expressed in a pattern where inflammatory illness was associated with increased expression in controls but not in subjects with schizophrenia. Schizophrenia was also associated with increased expression of Butyrophilin 2A2. HLA-A was expressed in glutamatergic and GABAergic neurons in the dentate gyrus, hilus, and the stratum pyramidale of the CA1-CA4 regions of the hippocampus, but not in astrocytes. In conclusion, the expression of genes from the major histocompatibility complex region of chromosome 6 with likely roles in synaptic development is altered in schizophrenia. There were also significant interactions between schizophrenia diagnosis and both inflammatory illness and smoking.

The α7 nicotinic acetylcholine receptor and the acute stress response: maternal genotype determines offspring phenotype.

α7 Nicotinic acetylcholine receptors (α7nAchRs) modulate immune activation by suppressing production of pro-inflammatory cytokines in peripheral immune cells. α7nAchRs also modulate inhibitory output in the hippocampus, which provides input to key circuits of the HPA axis. Therefore, the α7 nicotinic acetylcholine receptor gene (CHRNA7) may be associated with cortisol stress response. Polymorphisms in the CHRNA7 promoter decrease its expression and may dampen the cholinergic response, leading to an increase in inflammation. Increased inflammation may change the intrauterine environment, altering neuroendocrine development in the offspring. Maternal CHRNA7 genotype could affect an offspring's HPA regulation via reprogramming in utero. Patients with allergic disorders have a differential cortisol response to stress. This study utilized samples collected from a cohort of 198 adolescents in a previous study of atopic disorders, who demonstrated a disturbance in HPA response associated with atopy. Salivary cortisol samples collected from the adolescents after a series of laboratory procedures and DNA samples collected from the adolescents and their parents were used for further analysis. DNA samples were genotyped for allelic variation in the CHRNA7 promoter. Genetic association analyses with the cortisol levels were performed in the adolescents. Maternal genotype influences were investigated for the CHRNA7 gene. We also included maternal and child atopy diagnosis as covariates in determining cortisol levels and tested for association of CHRNA7 to atopy. Polymorphisms in the CHRNA7 promoter were associated with lower cortisol levels after a small laboratory stress. Our findings also show that although the child's CHRNA7 genotype affects stress response, the maternal genotype has a stronger influence on cortisol release after stress in male offspring. These effects were independent of atopy status.

A 2-base pair deletion polymorphism in the partial duplication of the alpha7 nicotinic acetylcholine gene (CHRFAM7A) on chromosome 15q14 is associated with schizophrenia.

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 alpha7 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.