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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Smoking is a common correlate of schizophrenia, which leads to medical morbidity. Although twin and adoption studies have consistently implicated genes in the etiology of both smoking and schizophrenia, finding genes has been difficult. Several authors have suggested that clinical or neurobiological features associated with schizophrenia, such as smoking, might improve the ability to detect schizophrenia susceptibility genes by identifying genes related to the etiology of that feature. The objective of this study is to assess evidence for linkage of sixteen nicotinic acetylcholine receptor genes and smoking in schizophrenia families, using data from the NIMH Genetics Initiative for schizophrenia. Sixteen nicotinic acetylcholine receptor genes were selected prior to analysis. We used a multipoint sibling pair linkage analysis program, SIBPAL2, with a smoking trait in schizophrenia families. The significance of the group of candidate genes, in addition to each individual candidate gene, was assessed using permutation testing, which adjusted for multiple comparisons. The group of genes showed significant linkage to the smoking trait after adjusting for multiple comparisons through permutation testing (p = 0.039). In addition, two of the individual candidate genes were significant (CHRNA2, p = 0.044) and (CHRNB2, p = 0.015) and two genes were marginally significant (CHRNA7, p = 0.095; CHRNA1, p = 0.076). The significance of the complex hypothesis, involving sixteen genes, implicates the nicotinic system in smoking for schizophrenic families. Individual gene analysis suggests that CHRNA2 and CHRNB2 may play a particular role in this involvement. Such findings help prioritize genes for future case control studies. In addition, we provide a novel permutation method that is useful in future analyses involving a single hypothesis, with multiple candidate genes.
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PMID:A novel permutation testing method implicates sixteen nicotinic acetylcholine receptor genes as risk factors for smoking in schizophrenia families. 1519 78

Biological traits that are predictive of the later development of psychosis have not yet been identified. The complex, multidetermined nature of schizophrenia and other psychoses makes it unlikely that any single biomarker will be both sensitive and specific enough to unambiguously identify individuals who will later become psychotic. However, current genetic research has begun to identify genes associated with schizophrenia, some of which have phenotypes that appear early in life. While these phenotypes have low predictive power for identifying individuals who will become psychotic, they do serve as biomarkers for pathophysiological processes that can become the targets of prevention strategies. Examples are given from work on the role of the alpha(T)nicotinic receptor and its gene CHRNA7 on chromosome 15 in the neurobiology and genetic transmission of schizophrenia.
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PMID:Early biomarkers of psychosis. 1606 May 93

Evidence of genetic linkage for schizophrenia at chromosome 15q14 has been reported in nine independent studies, but the molecular variants responsible for transmission of genetic risk are unknown. National Institute of Mental Health Schizophrenia Genetics Initiative families were genotyped for single nucleotide polymorphisms (SNPs) and dinucleotide repeat markers in the 15q14 linkage region and analyzed based on the presence of particular alleles of the dinucleotide repeat marker D15S165 in the 15q14 region. Two alleles showed both familial transmission disequilibrium and population-wide association with schizophrenia. The two groups identified by these two D15S165 alleles differ in age of onset, number of hospitalizations and intensity of nicotine abuse, as well as in predominant ethnicity. Variations in the frequency of SNPs in CHRNA7, the alpha-7-nicotinic acetylcholine receptor subunit gene at 15q14, were found in each group. Further sequencing in these two groups may yield more definitive identification of the molecular pathology.
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PMID:Characterization of allelic variants at chromosome 15q14 in schizophrenia. 1641 13

The human alpha-7 neuronal nicotinic receptor subunit (CHRNA7) gene, located at chromosome 15q13.2, represents a strong candidate gene for schizophrenia. We have examined an (AC)n dinucleotide repeat in intron 2 of the CHRNA7 gene, which was previously shown to be strongly linked with schizophrenia, using both population-based and family-based association studies. In the population-based study, no significant differences between the genotype and allele frequency distributions in schizophrenia patients and control subjects were observed after correction for multiple testing, although a nominally significant association between the most common allele and schizophrenia was observed (P = 0.023, uncorrected for multiple testing). In the family-based study, there is no significant over-transmission (Transmitted/Non-transmitted: 61/50) of the same allele in 160 family trios. Overall, our results do not support a major role for the (AC)n dinucleotide repeat in schizophrenia susceptibility in Han Chinese. Further large-scale genetic studies based on a set of single nucleotide polymorphisms (SNPs) that fully characterize the linkage disequilibrium patterns at the CHRNA7 gene are necessary to determine the relevance of this gene as a risk factor for schizophrenia susceptibility.
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PMID:Population-based and family-based association studies of an (AC)n dinucleotide repeat in alpha-7 nicotinic receptor subunit gene and schizophrenia. 1656 1

Neurodevelopmental changes may underlie the brain dysfunction seen in schizophrenia. While advances have been made in our understanding of the genetics of schizophrenia, little is known about how non-genetic factors interact with genes for schizophrenia. The present analysis of genes potentially associated with schizophrenia is based on the observation that hypoxia prevails in the embryonic and fetal brain, and that interactions between neuronal genes, molecular regulators of hypoxia, such as hypoxia-inducible factor 1 (HIF-1), and intrinsic hypoxia occur in the developing brain and may create the conditions for complex changes in neurodevelopment. Consequently, we searched the literature for currently hypothesized candidate genes for susceptibility to schizophrenia that may be subject to ischemia-hypoxia regulation and/or associated with vascular expression. Genes were considered when at least two independent reports of a significant association with schizophrenia had appeared in the literature. The analysis showed that more than 50% of these genes, particularly AKT1, BDNF, CAPON, CCKAR, CHRNA7, CNR1, COMT, DNTBP1, GAD1, GRM3, IL10, MLC1, NOTCH4, NRG1, NR4A2/NURR1, PRODH, RELN, RGS4, RTN4/NOGO and TNF, are subject to regulation by hypoxia and/or are expressed in the vasculature. Future studies of genes proposed as candidates for susceptibility to schizophrenia should include their possible regulation by physiological or pathological hypoxia during development as well as their potential role in cerebral vascular function.
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PMID:Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. 1663 32

Schizophrenia and bipolar disorder are major psychiatric diseases that have a strong genetic element. Markers in the vicinity of the CHRNA7 gene at 15q13-q14 have been linked with an endophenotype of schizophrenia, P50 sensory gating disorder, with schizophrenia itself and with bipolar disorder. We have measured the copy number of the polymorphic partial duplication of CHRNA7 (CHRFAM7A) and genotyped a polymorphic 2 bp deletion within exon 6 of CHRFAM7A. In this study, 208 probands with a primary diagnosis of schizophrenia, 217 with a diagnosis of bipolar affective disorder and 28 with schizoaffective or other psychotic disorders were examined together with 197 controls recruited from the same region in Scotland. No significant association was seen for schizophrenia and bipolar disorder by genotype or allele overall for either polymorphism, but a mildly significant association by genotype (P = 0.04) was observed for absence of CHRFAM7A when the sample was analyzed as a single psychosis phenotype.
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PMID:Association study of CHRFAM7A copy number and 2 bp deletion polymorphisms with schizophrenia and bipolar affective disorder. 1682 4

Positive genetic linkage to the 15q13-q14 region has been found in 11 studies, and several association reports support this locus as a candidate region for schizophrenia. The locus is unusual in that it was first linked to an endophenotype found in schizophrenia, the P50 deficit, and subsequently to schizophrenia. There is also biological data showing that a candidate gene in the region, the alpha7 nicotinic receptor CHRNA7, plays a seminal role in the linked endophenotype, and is decreased in expression in the patient population. The 15q13-q14 region is complicated by a partial duplication of the CHRNA7 gene that includes exons 5-10 and considerable sequence downstream. Evidence from multiple studies supports a broad region of genetic linkage around the marker D15S1360.
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PMID:Genetics of chromosome 15q13-q14 in schizophrenia. 1684 94

Patients with schizophrenia exhibit deficits in a range of cognitive functions, particularly working and episodic memory, which are thought to be core features of the disorder. Memory dysfunction in schizophrenia is familial and thus a promising endophenotype for genetic studies. Both human and animal studies suggest a role for the neural nicotinic acid receptor family in cognition and specifically the alpha7-receptor subunit in schizophrenia and its endophenotypes. Consequently, we tested mice lacking the alpha7 subunit of the neural nicotinic receptor (B6.129S7-Chrna7(tm1Bay)/J) in the delayed matching-to-place (DMP) task of the Morris water maze, a measure of working/episodic memory akin to human episodic memory. We report that a minor impairment in alpha7 knockout mice was observed in the DMP task, with knockout mice taking longer to find the hidden platform than their wildtype controls. This suggests a role for the alpha7 subunit in working/episodic memory and a potential role for the alpha7 neural nicotinic receptor gene (CHRNA7) in schizophrenia and its endophenotypes.
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PMID:Performance deficit of alpha7 nicotinic receptor knockout mice in a delayed matching-to-place task suggests a mild impairment of working/episodic-like memory. 1692 47

Several previous studies have reported a significant linkage between markers in the alpha 7 nicotinic cholinergic receptor subunit (CHRNA7) gene and either schizophrenia or the P50 sensory gating deficit, a schizophrenia endophenotype. However, CHRFAM7A, a partially duplicated gene 1.6Mb upstream of the CHRNA7 gene, has complicated further genetic analysis. We genotyped 14 polymorphic markers throughout the full-length CHRNA7 gene and the duplicated region in 188 unrelated Han Chinese patients with schizophrenia and 188 controls. The duplicated regions were assessed by genotyping up- and down-stream polymorphic markers in the vicinity of each region and analyzing the linkage disequilibrium (LD) between each pair of markers. No evidence of risk variants for schizophrenia in either the CHRNA7 gene or the partially duplicated region was found in the LD analysis. A significant deviation from the Hardy-Weinberg equilibrium (HWE) was found only in the genotypic distribution of SNP9 (IVS4-1912) in patients (p=0.00829), but not in controls. In conclusion, our LD analysis did not reveal any association between schizophrenia in our Han Chinese population and the CHRNA7 gene or its partially duplicated region. However, we could not exclude the possibility of a weak genetic effect due to the small sample size. Analyses of larger samples and higher-density markers, particularly around SNP9 (IVS4-1912), are still needed.
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PMID:Linkage disequilibrium analysis of the CHRNA7 gene and its partially duplicated region in schizophrenia. 1711 75

The author reviews relevant data on the neuropathology and molecular genetics of schizophrenia. Anatomical alterations are localized mainly in the hippocampus, dorsal thalamus and dorsolateral prefrontal cortex, and involve the morphology and molecular structure of the neurons and synapses. Several susceptibility genes [including COMT, dysbindin, neuregulin, DISCI, RGS4, GRM3, G72, PPP3CC, CHRNA7, PRODH2, Aktl, 5qGABA(A)] having physiological function in the brain have been identified and this supports the view of schizophrenia as a disorder of cerebral synaptic function. NMDA receptor-mediated glutamate transmission may be particularly involved, but disturbances of dopamine and GABA signalling seem to be linked as well. Based on recent data, an agreement is emerging between the roles of the genes on the molecular and synaptic levels and the understanding of the disorder at the neural systems level.
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PMID:[Gene polymorphism and gene expression in schizophrenia]. 1743 57


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