The results of this large-scale exome sequencing of patients and controls shed light on both well-established and controversial non-BRCA predisposition gene associations with breast or ovarian cancer reported to date and may implicate additional breast or ovarian cancer susceptibility gene candidates involved in DNA repair and genomic maintenance.

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The α7 neuronal nicotinic receptor gene (CHRNA7) has been implicated in the pathophysiology of schizophrenia by genetic and pharmacological studies. Expression of the α7* receptor, as measured by [ 125 I]α-bungarotoxin autoradiography, is decreased in postmortem brain of schizophrenic subjects compared to non-mentally ill controls. Most schizophrenic patients are heavy smokers, with high levels of serum cotinine. Smoking changes the expression of multiple genes and differentially regulates gene expression in schizophrenic hippocampus. We examined the effects of smoking on CHRNA7 expression in the same tissue and find that smoking differentially regulates expression of both mRNA and protein for this gene. CHRNA7 mRNA and protein levels are significantly lower in schizophrenic nonsmokers compared to control nonsmokers and are brought to control levels in schizophrenic smokers. Sufficient protein but low surface expression of the α7* receptor, seen in the autoradiographic studies, suggests aberrant assembly or trafficking of the receptor.

Cognitive deficits in schizophrenia are a major source of dysfunction for which more effective treatments are needed. The vasopressin-deficient Brattleboro (BRAT) rat has been shown to have several natural schizophrenia-like deficits, including impairments in prepulse inhibition and memory. We investigated BRAT rats and their parental strain, Long Evans (LE) rats, in a social discrimination paradigm, which is an ethologically-relevant animal test of cognitive deficits of schizophrenia based upon the natural preference of animals to investigate conspecifics. We also investigated the effects of the atypical antipsychotic, clozapine and the putative antipsychotic, PD149163, a brain-penetrating neurotensin-1 analogue, on social discrimination in these rats. Adult rats were administered saline or one of three doses of clozapine (0.1, 1.0 or 10 mg/kg) or PD149163 (0.1, 0.3 or 1.0 mg/kg), subcutaneously. Following drug administration, adult rats were exposed to a juvenile rat for a 4-minute learning period. Animals were then housed individually for 30 minutes and then simultaneously exposed to the previously presented juvenile and a new juvenile for 4 minutes. Saline-treated LE rats, but not BRAT rats, exhibited intact social discrimination as evidenced by greater time spent exploring the new juvenile. The highest dose of clozapine and the two highest doses of PD149163 restored social discrimination in BRAT rats. These results provide further support for the utility of the BRAT rat as a genetic animal model relevant to schizophrenia and drug discovery. The potential of neurotensin agonists as putative treatments for cognitive deficits of schizophrenia was also supported.

Schizophrenia is a common mental illness with a high prevalence of smoking. More than 80% of schizophrenics smoke compared to 25% of the general population. Both schizophrenia and tobacco use have strong genetic components, which may overlap. It has been suggested that smoking in schizophrenia may be a form of self-medication in an attempt to treat an underlying biological pathology. Smoking normalizes auditory evoked potential and eye tracking deficits in schizophrenia, as well as improving cognitive function. Nicotine acts through a family of nicotinic receptors with either high or low affinity for nicotine. The loci for several of these receptors have been genetically linked to both smoking and to schizophrenia. Smoking changes gene expression for more than 200 genes in human hippocampus, and differentially normalizes aberrant gene expression in schizophrenia. The α7* nicotinic receptor, linked to schizophrenia and smoking, has been implicated in sensory processing deficits and is important for cognition and protection from neurotoxicity. Nicotine, however, has multiple health risks and desensitizes the receptor. A Phase I trial of DMXB-A, an α7* agonist, shows improvement in both P50 gating and in cognition, suggesting that further development of nicotinic cholinergic drugs is a promising direction in schizophrenia research.Schizophrenia and smoking are closely connected. The prevalence of tobacco use in schizophrenia is inordinately high. Only 25% of the general population now smokes, but more than 80% of schizophrenics use tobacco products (de Leon and Diaz, 2005;Diwan et al

The αN-catenin (CTNNA2) gene represents a promising candidate gene for schizophrenia based upon previous genetic linkage, expression, and mouse knockout studies. CTNNA2 is differentially regulated by smoking in schizophrenic patients. In this report, the genomic structure of a primatespecific αN-catenin splice variant (αN-catenin III) is described. A comparison of αN-catenin III mRNA expression across postmortem hippocampi from schizophrenic and non-mentally ill smokers and non-smokers revealed a significant decrease in expression among patient non-smokers compared to all other groups. The recent evolutionary divergence of this gene, as well as the differences in gene expression in postmortem brain of schizophrenic non-smokers, supports the role of αN-catenin III as a novel disease susceptibility gene.

Inbred mouse strains display significant differences in their levels of brain ␣7 nicotinic acetylcholine receptor (␣7 nAChR) expression, as measured by binding of the ␣7-selective antagonist ␣-bungarotoxin. Variations in ␣-bungarotoxin binding have been shown to correlate with an animal's sensitivity to nicotine-induced seizures and sensory gating. In two inbred mouse strains, C3H/2Ibg (C3H) and DBA/2Ibg (DBA/2), the interstrain binding differences are linked to a restriction length polymorphism in the ␣7 nAChR gene, Chrna7. Despite this finding, the molecular mechanism(s) through which genetic variability in Chrna7 may contribute to ␣7 nAChR expression differences remains unknown. However, studies of the human ␣7 nAChR gene (CHRNA7) previously have demonstrated that CHRNA7 promoter polymorphisms are associated with differences in promoter activity as well as differences in sensory processing. In the present study, a 947-base pair region of the Chrna7 promoter was cloned from both the C3H and DBA/2 inbred mouse strains in an attempt to identify polymorphisms that may underlie ␣7 nAChR differential expression. Sequence analysis of these fragments identified 14 single nucleotide polymorphisms (SNPs). A combination of two of these SNPs affects promoter activity in an in vitro luciferase reporter assay. These results suggest a mechanism through which the Chrna7 promoter genotype may influence interstrain variations in ␣7 nAChR expression.The expression of ␣7 nAChRs, 3 as measured by 125 I-labeled ␣-bungarotoxin (␣-BTX), varies significantly across inbred mouse strains (1, 2), and studies have demonstrated that interstrain differences in ␣7 nAChR expression are genetically regulated. For example, restriction fragment length polymorphisms in Chrna7, the gene that encodes for the mouse ␣7 nAChR subunit, have been shown to be linked to ␣7 nAChR expression in genetically segregating populations derived from the inbred mouse strains C3H and DBA/2 (3). The strain differences in binding appear to be related to differences in ␣7 nicotinic receptor mRNA levels (2, 4), suggesting that transcriptional or posttranscriptional mechanisms may contribute to the variations in ␣-BTX expression levels.Genetically regulated ␣7 nicotinic receptor expression patterns have been associated with individual variations in neurophysiology and neuroanatomy. Interstrain differences in ␣-BTX binding are related to variations in sensitivity to nicotine-induced seizures, acoustic startle response (5), and hippocampal sensory gating (2). In addition, genetic variability in Chrna7 has been implicated in regulating individual differences in cholinergic and GABAergic hippocampal neuroanatomy (6 -8).Variations in ␣-BTX binding have also been associated with differences in neurophysiological function among humans. Schizophrenics, for example, display reduced ␣-BTX binding levels in post-mortem hippocampus (9). Furthermore, promoter polymorphisms in the gene coding for the human ␣7 nAChR subunit are associated with an auditory gating deficit that is common...