| 1 | Psychiatr. Genet. 2003 Jun 13: 91-5 |
|---|---|
| PMID | 12782965 |
| Title | Schizophrenia, psychotic illness and other psychiatric symptoms in families with autosomal dominant nocturnal frontal lobe epilepsy caused by different mutations. |
| Abstract | Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by a strong family history of epileptic seizures, which predominantly occur during sleep. ADNFLE has been associated with mutations in two genes coding for the nicotinic acetylcholine receptor (CHRNA4 and CHRNB2). Thus far, three different mutations have been detected in the CHRNA4 gene, and two in the CHRNB2 gene. The aim of this study was to compare the frequency of psychiatric disorders in two ADNFLE families with different CHRNA4 mutations (776ins3 and Ser248Phe). Information was gathered from hospital charts and therapists, and the family members were assessed by clinical interviews and structured clinical interviews. Of the 10 individuals diagnosed with epilepsy in the CHRNA4-776ins3 family, at least four had been in contact with psychiatric services. One individual had schizophrenia, while another family member had experienced at least two severe psychotic episodes, and had been taking antipsychotic medications for years. The third family member had been hospitalized at least three times for psychiatric problems. The fourth family member needs help with activities of daily living due to incapacitating apathy, although she does not have a psychiatric diagnosis. Such accumulation of psychiatric problems was not seen in the family with the Ser248Phe mutation. These findings suggest that there may be an association between the 776ins3 mutation and the psychiatric symptoms, a hypothesis that needs further testing. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Exp Brain Res 2006 Sep 174: 292-6 |
| PMID | 16636791 |
| Title | Genetic interaction between alpha4 and beta2 subunits of high affinity nicotinic receptor: analysis in schizophrenia. |
| Abstract | Cholinergic dysfunction is one of the hypotheses for the cognitive deficits of schizophrenia. Neurocognitive deficits, which are well-described clinical features of schizophrenia, may be remediated by nicotine; therefore investigations of nicotinic receptor subtypes is of considerable clinical interest. We typed polymorphisms in CHRNA4 and CHRNB2 genes controlling the expression of neuronal high-affinity nicotinic receptors in 117 Canadian families having at least one schizophrenic patient. Using a family-based association strategy, we performed allele, haplotype and interaction analysis of these two loci. In the families tested, the two cholinergic genes interact to affect schizophrenia in combination (P=0.010), while neither was sufficient alone to confer susceptibility. Our present study provided the first line of direct evidence suggesting that the CHRNA4 gene combined with CHRNB2 receptor gene may be linked to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Exp Brain Res 2006 Sep 174: 292-6 |
| PMID | 16636791 |
| Title | Genetic interaction between alpha4 and beta2 subunits of high affinity nicotinic receptor: analysis in schizophrenia. |
| Abstract | Cholinergic dysfunction is one of the hypotheses for the cognitive deficits of schizophrenia. Neurocognitive deficits, which are well-described clinical features of schizophrenia, may be remediated by nicotine; therefore investigations of nicotinic receptor subtypes is of considerable clinical interest. We typed polymorphisms in CHRNA4 and CHRNB2 genes controlling the expression of neuronal high-affinity nicotinic receptors in 117 Canadian families having at least one schizophrenic patient. Using a family-based association strategy, we performed allele, haplotype and interaction analysis of these two loci. In the families tested, the two cholinergic genes interact to affect schizophrenia in combination (P=0.010), while neither was sufficient alone to confer susceptibility. Our present study provided the first line of direct evidence suggesting that the CHRNA4 gene combined with CHRNB2 receptor gene may be linked to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Biochem. Pharmacol. 2007 Oct 74: 1308-14 |
| PMID | 17662253 |
| Title | The role of the nicotinic acetylcholine receptors in sleep-related epilepsy. |
| Abstract | The role of neuronal acetylcholine receptors (nAChRs) in epilepsy has been clearly established by the finding of mutations in a subset of genes coding for subunits of the nAChRs in a form of sleep-related epilepsy with familial occurrence in about 30% of probands and dominant inheritance, named autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Sporadic and familial forms have similar clinical and EEG features. Seizures begin in middle childhood as clusters of sleep-related attacks with prominent motor activity, and sustained dystonic posturing. In addition to nocturnal seizures, psychosis or schizophrenia, behavioral disorders, memory deficits and mental retardation were described in some individuals. Although over hundred families are on record, only a minority of them have been linked to mutations in the genes coding for the alpha4, alpha2 and beta2 (CHRNA4, CHRNA2, and CHRNB2) subunits of the nAChRs, indicating that ADNFLE is genetically heterogeneous despite a relatively homogeneous clinical picture. Functional characterization of some mutations suggests that gain of the receptor function might be the basis for epileptogenesis. In vitro and in vivo studies have shown high density of nAChRs in the thalamus, over activated brainstem ascending cholinergic pathway and enhanced GABAergic function, reinforcing the hypothesis that cortico-subcortical networks, regulating arousal from sleep, play a central role in seizure precipitation in ADNFLE. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | J Psychiatry Neurosci 2007 Nov 32: 412-6 |
| PMID | 18043764 |
| Title | Association of alpha4beta2 nicotinic receptor and heavy smoking in schizophrenia. |
| Abstract | Previously we suggested that the CHRNA7 polymorphism in nicotinic receptor genes, in particular the D15S1360 in CHRNA7, is associated with smoking in schizophrenia. schizophrenia patients are usually heavy smokers. In this study we hypothesized that high-affinity nicotinic receptors are associated with smoking in such patients. To investigate the role of alpha4 (Ch 20) and beta2 (Ch 1) genes in conferring a risk for smoking and for smoking a large number of cigarettes daily in subjects with schizophrenia. Our study sample consisted of 241 white European schizophrenia patients (157 smokers and 84 nonsmokers) from the Toronto area. Current smoking status was assessed by the medical history. We investigated 4 markers located in the CHRNA4 gene and 3 markers located in the CHRNB2 gene. There was no difference in age or ethnicity between the 2 groups and the population was not stratified (lambda=0.4527). We found a significant association between the CHRNA4 rs3746372 allele 1 and a large number of cigarettes smoked daily (p=0.0203). The intragenic interaction between rs3787116 and rs3746372 (p = 0.0050) in CHRNA4 showed a significant interaction for the number of cigarettes smoked. Although our findings suggest an association between rs3746372 allele 1 and heavy smoking, further study is warranted to investigate the relation between smoking and high-affinity nicotinic receptor genes in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Ann. N. Y. Acad. Sci. 2008 -1 1129: 200-12 |
| PMID | 18591481 |
| Title | Molecular genetics of attention. |
| Abstract | The sequencing of the human genome and the identification of a vast array of DNA polymorphisms has afforded cognitive scientists with the opportunity to interrogate the genetic basis of cognition with renewed vigor. The extant literature on the molecular genetics of sustained and spatial attention is reviewed herein. Advances in our understanding of the neural substrates of sustained and spatial attention arising from the cognitive neurosciences can help guide putative linkages in cognitive genetics. In line with catecholamine models of sustained attention, associations have been reported between sustained attention and allelic variation in the dopamine beta hydroxylase gene (DBH), the dopamine D2 and D4 receptor genes (DRD2; DRD4) and the dopamine transporter gene (DAT1). Much evidence implicates the cholinergic system in spatial attention. Accordingly, individual differences in spatial attention have been associated with variation in an alpha-4 cholinergic receptor gene (CHRNA4). APOE-epsilon4 allele dosage has been shown to influence the speed of attentional reorienting in independent samples of nonaffected individuals. Preliminary evidence in both healthy children and children with attention deficit hyperactivity disorder (ADHD) suggests and association with variants of the DAT1 gene and the control of spatial attention across the hemifields. With the recent development of high-throughput genotyping techniques, such as microarrays, the time seems ripe for a genomewide association study that can identify quantitative trait loci (QTLs) for sustained and spatial attention. The identification of QTLs for attention will provide a range of novel candidate genes for disorders of attention, such as ADHD and schizophrenia, and will drive cognitive neuroscientists to understand how DNA variation influences the neural substrates of attention. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | J Neural Transm (Vienna) 2008 Oct 115: 1457-61 |
| PMID | 18762859 |
| Title | Genetic association analysis of tagging SNPs in alpha4 and beta2 subunits of neuronal nicotinic acetylcholine receptor genes (CHRNA4 and CHRNB2) with schizophrenia in the Japanese population. |
| Abstract | Several lines of evidence suggest that nicotinic cholinergic dysfunction may contribute to the cognitive impairments in schizophrenia. The majority of high affinity nicotine binding sites in the human brain have been implicated in heteropentameric alpha4 and beta2 subunits of neuronal nicotinic acetylcholine receptors; therefore, these two neuronal nicotinic acetylcholine receptors genes (CHRNA4 and CHRNB2) are considered to be attractive candidate genes for the pathophysiology of schizophrenia. To represent these two genes in a gene-wide manner, we first evaluated the linkage disequilibrium structure using our own control samples. Thirteen SNPs (7 SNPs for CHRNA4 and 5 SNPs for CHRNB2) were selected as tagging SNPs. Using these tagging SNPs, we then conducted genetic association analysis of case-control samples (738 schizophrenia and 753 controls) in the Japanese population. No significant association was detected in the allele/genotype-wise or haplotype-wise analysis. Our results suggest that CHRNA4 and CHRNB2 do not play a major role in Japanese schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | J Cogn Neurosci 2010 Sep 22: 1944-54 |
| PMID | 19803686 |
| Title | The association between dopamine DRD2 polymorphisms and working memory capacity is modulated by a functional polymorphism on the nicotinic receptor gene CHRNA4. |
| Abstract | Working memory capacity is extremely limited and individual differences are heritable to a considerable extent. In the search for a better understanding of the exact genetic underpinnings of working memory, most research has focused on functional gene variants involved in the metabolism of the neurotransmitter dopamine. Recently, there has been investigation of genes related to other neurotransmitter systems such as acetylcholine. The potential relevance of a polymorphism located in the gene coding for the alpha4 subunit of the nicotinic acetylcholine receptor (rs#1044396) has been discussed with respect to working memory, but empirical investigations have provided mixed results. However, pharmacological studies in both rodents and humans have shown that the effect of nicotinic agonists on cognitive functions is mediated by dopamine. We therefore hypothesized that such an interaction can be found on a molecular genetic level as well. In order to test this hypothesis, we genotyped 101 healthy subjects for rs#1044396 and three functional polymorphisms on the dopamine d2 receptor gene (rs#1800497, rs#6277, rs#2283265). These subjects performed a visuospatial working memory task in which memory load was systematically varied. We found a significant interaction between rs#1044396 and a haplotype block covering all three dopaminergic polymorphisms on working memory capacity. This effect only became apparent on higher levels of working memory load. This is the first evidence from a molecular genetic perspective that these two neurotransmitter systems interact on cognitive functioning. The results are discussed with regard to their implication for working memory theories and their clinical relevance for treatment of substance abuse and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Seizure 2012 Mar 21: 118-23 |
| PMID | 22036597 |
| Title | Mutations in familial nocturnal frontal lobe epilepsy might be associated with distinct neurological phenotypes. |
| Abstract | Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a rare familial seizure disorder caused by mutations in at least two different subunit genes of the neuronal nicotinic acetylcholine receptor (nAChR), CHRNA4 and CHRNB2. ADNFLE was initially described as a "pure" seizure disorder with a mostly benign course. We have analysed the clinical features of 19 ADNFLE families from 12 countries with a total of 150 patients and grouped them with respect to their nAChR mutations. These data suggest that certain nAChR mutations might be associated with an increased risk for major neurological symptoms such as mental retardation, schizophrenia-like symptoms or marked cognitive deficits, but the risk for these disorders seems to be low for most other ADNFLE mutations. The functional data confirm that the mutations differ from each other with respect to the size of their gain-of function effects and other biopharmacological characteristics although these functional changes are not predictive for the severity of the clinical phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Hum Psychopharmacol 2013 May 28: 220-9 |
| PMID | 23553665 |
| Title | Relationship between nicotine dependence and the endophenotype-related trait of cognitive function but not acoustic startle reponses in Japanese patients with schizophrenia. |
| Abstract | We investigated whether nicotine dependence affects these endophenotypes in Japanese schizophrenia patients and whether alpha4 and beta2 subunits of neuronal nicotinic acetylcholine receptor genes (alpha4 subunit of the nAChR gene (CHRNA4)/beta2 subunit of the nAChR gene (CHRNB2)) were associated with nicotine dependence in patients (n?=?100) and healthy controls (n?=?107). First, in patients, we evaluated cognitive function, using the Brief Assessment of Cognition in schizophrenia, and acoustic startle responses. Second, we evaluated the severity of nicotine dependence, using the Tobacco Dependence Screener, the Fagerström Test for Nicotine Dependence, and the Brinkman index in current smokers in both groups. Third, we evaluated the relationship between acoustic startle responses, cognitive function, and severity of nicotine dependence. Finally, using 12 tagging single-nucleotide polymorphisms in each the CHRNA4/CHRNB2, we used multiple linear regression analysis to examine the association between nicotine dependence measures and each selected single-nucleotide polymorphism. The presence and severity of nicotine dependence were associated with verbal memory and executive function in schizophrenia patients. However, nicotine dependence was not correlated with any acoustic startle response. In addition, rs755203 and rs1044397 in CHRNA4 were associated with nicotine dependence in healthy controls. Nicotine dependence might influence the level of verbal memory and executive function in schizophrenia patients. In addition, rs755203 and rs1044397 in CHRNA4 might play a role in the pathophysiology of nicotine dependence in healthy controls in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | BMC Genet. 2015 -1 16: 46 |
| PMID | 25934188 |
| Title | The nicotinic acetylcholine receptor alpha 4 subunit contains a functionally relevant SNP Haplotype. |
| Abstract | Non-coding single nucleotide polymorphisms within the nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4) are robustly associated with various neurological and behavioral phenotypes including schizophrenia, cognition and smoking. The most commonly associated polymorphisms are located in exon 5 and segregate as part of a haplotype. So far it is unknown if this haplotype is indeed functional, or if the observed associations are an indirect effect caused by linkage disequilibrium with not yet identified adjacent functional variants. We therefore analyzed the functional relevance of the exon 5 haplotype alleles. Using voltage clamp experiments we were able to show that the CHRNA4 haplotype alleles differ with respect to their functional effects on receptor sensitivity including reversal of receptor sensitivity between low and high acetylcholine concentrations. The results indicate that underlying mechanisms might include differences in codon usage bias and changes in mRNA stability. Our data demonstrate that the complementary alleles of the CHRNA4 exon 5 haplotype are functionally relevant, and might therefore be causative for the above mentioned associations. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Cogn Neuropsychiatry 2016 Mar 21: 156-67 |
| PMID | 26982087 |
| Title | CHRNA4 was associated with prepulse inhibition of schizophrenia in Chinese: a pilot study. |
| Abstract | Prepulse inhibition (PPI) of the auditory startle reflex, as an operational measurement used to evaluate the function of brain sensorimotor gating, appears to be a sensitive potential endophenotype for schizophrenia. CHRNA4 is highly expressed in the central nervous system and has been demonstrated to be significantly associated with schizophrenia by previous studies. The purpose of the current study was to evaluate the effect of CHRNA4 on PPI and acoustic startle parameters in schizophrenia. 77 patients with schizophrenia and 62 controls were administered the test PPI, and 3 single nucleotide polymorphisms (SNPs) (rs3746372, rs1044396, and rs3787140) of CHRNA4 were genotyped in these subjects. Patients with schizophrenia showed significantly lower levels of PPI at the 120?ms prepulse intervals and longer peak latency than controls, and the GG genotype of rs3746372 and the TT genotype of rs1044396 were associated with decreased PPI levels in schizophrenia but not in controls. PPI may be influenced by the polymorphisms of the CHRNA4 in schizophrenia and it may be a potential endophenotype of schizophrenia. An independent replication would greatly increase the value of this study. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Neurosci. Lett. 2016 Jun 623: 36-41 |
| PMID | 27109789 |
| Title | Cholinergic modulation of auditory P3 event-related potentials as indexed by CHRNA4 and CHRNA7 genotype variation in healthy volunteers. |
| Abstract | schizophrenia (SZ) is a psychiatric disorder characterized by cognitive dysfunction within the realm of attentional processing. Reduced P3a and P3b event-related potentials (ERPs), indexing involuntary and voluntary attentional processing respectively, have been consistently observed in SZ patients who also express prominent cholinergic deficiencies. The involvement of the brain's cholinergic system in attention has been examined for several decades; however, further inquiry is required to further comprehend how abnormalities in this system affect neighbouring neurotransmitter systems and contribute to neurocognitive deficits. The objective of this pilot study was to examine the moderating role of the CHRNA4 (rs1044396), CHRNA7 (rs3087454), and SLC5A7 (rs1013940) genes on ERP indices of attentional processing in healthy volunteers (N=99; Caucasians and non-Caucasians) stratified by genotype and assessed using the auditory P300 "oddball" paradigm. Results indicated significantly greater P3a and P3b-indexed attentional processing for CT (vs. CC) CHRNA4 carriers and greater P3b for AA (vs. CC) CHRNA7 carriers. SLC5A7 allelic variants did not show significant differences in P3a and P3b processing. These findings expand our knowledge on the moderating effect of cholinergic genes on attention and could help inform targeted drug developments aimed at restoring attention deficits in SZ patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 14 | PLoS ONE 2016 -1 11: e0152984 |
| PMID | 27054571 |
| Title | Association of Common Polymorphisms in the Nicotinic Acetylcholine Receptor Alpha4 Subunit Gene with an Electrophysiological Endophenotype in a Large Population-Based Sample. |
| Abstract | Variation in genes coding for nicotinic acetylcholine receptor (nAChR) subunits affect cognitive processes and may contribute to the genetic architecture of neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in the CHRNA4 gene that codes for the alpha4 subunit of alpha4/beta2-containing receptors have previously been implicated in aspects of (mostly visual) attention and smoking-related behavioral measures. Here we investigated the effects of six synonymous but functional CHRNA4 exon 5 SNPs on the N100 event-related potential (ERP), an electrophysiological endophenotype elicited by a standard auditory oddball. A total of N = 1,705 subjects randomly selected from the general population were studied with electroencephalography (EEG) as part of the German Multicenter Study on nicotine addiction. Two of the six variants, rs1044396 and neighboring rs1044397, were significantly associated with N100 amplitude. This effect was pronounced in females where we also observed an effect on reaction time. Sequencing of the complete exon 5 region in the population sample excluded the existence of additional/functional variants that may be responsible for the observed effects. This is the first large-scale population-based study investigation the effects of CHRNA4 SNPs on brain activity measures related to stimulus processing and attention. Our results provide further evidence that common synonymous CHRNA4 exon 5 SNPs affect cognitive processes and suggest that they also play a role in the auditory system. As N100 amplitude reduction is considered a schizophrenia-related endophenotype the SNPs studied here may also be associated with schizophrenia outcome measures. |
| SCZ Keywords | schizophrenia, schizophrenic |