Fine-mapping reveals novel alternative splicing of the dopamine transporter

Center for Human Genetic Research, Massachusetts General Hospital and Department of Neurology, Harvard Medical School, Harvard University, Boston, Massachusetts.Graduate Program in Biology and Biomedical Science, Yale University, New Haven, Connecticut.The dopamine transporter gene (, ) has been implicated in the pathogenesis of numerous psychiatric and neurodevelopmental disorders, including schizophrenia (SZ). We previously detected association between SZ and intronic variants that replicated in two independent Caucasian samples, but had no obvious function. In follow-up analyses, we sequenced the coding and intronic regions of to identify complete linkage disequilibrium patterns of common variations. We genotyped 78 polymorphisms, narrowing the potentially causal region to two correlated clusters of associated SNPs localized predominantly to introns 3 and 4. Our computational analysis of these intronic regions predicted a novel cassette exon within intron 3, designated E3b, which is conserved among primates. We confirmed alternative splicing of E3b in post-mortem human substantia nigra (SN). As E3b introduces multiple in-frame stop codons, the open reading frame is truncated and the spliced product may undergo nonsense mediated decay. Thus, factors that increase E3b splicing could reduce the amount of unspliced product available for translation. Observations consistent with this prediction were made using cellular assays and in post-mortem human SN. In mini-gene constructs, the extent of splicing is also influenced by at least two common haplotypes, so the alternative splicing was evaluated in relation to SZ risk. Meta-analyses across genome-wide association studies did not support the initial associations and further post-mortem studies did not suggest case-control differences in splicing. These studies do not provide a compelling link to schizophrenia. However, the impact of the alternative splicing on other neuropsychiatric disorders should be investigated. © 2010 Wiley-Liss, Inc

Morphology of the orbitofrontal cortex in first-episode schizophrenia: Relationship with negative symptomatology

Different studies have documented OFC abnormalities in schizophrenia, but it is unclear if they are present at disease onset or are a consequence of disease process and/or drug exposure. the evaluation of first-episode, drug-naive subjects allows us to clarify this issue. Magnetic resonance imaging was performed on 43 first-episode, antipsychotic-naive schizophrenia patients and 53 healthy comparison subjects matched for age, gender, race, and handedness. Gray matter OFC volumes were measured blind to the diagnoses. As compared to controls, patients had greater volumes in left total OFC (p=0.048) and left lateral OFC (p=0.037). Severity of negative symptoms (anhedonia, flattened affect, and alogia) positively correlated with both the left lateral (Spearman's, rho=0.37, p=0.019; rho=0.317, p=0.041; r=0.307, p=0.048, respectively) and the left total OFC (Spearman's, rho=0.384, p=0.014; rho=0.349, p=0.023; rho=0.309, p=0.047, respectively). the present results suggest that first-episode, antipsychotic-naive schizophrenia subjects exhibit increased OFC volumes that correlate with negative symptoms severity. the OFC, through extensive and complex interconnections with several brain structures with putative role in pathophysiology of schizophrenia including amygdala, hippocampus, thalamus, DLPFC, and superior temporal lobe, may mediate schizophrenia symptoms such as blunting of emotional affect and impaired social functioning. Although the specific neuropathological mechanisms underlying structural abnormalities of the OFC remain unclear, increased OFC volumes might be related to deviations in neuronal migration and/or pruning. Future follow-up studies examining high-risk individuals who subsequently develop schizophrenia at different stages of disease could be especially instructive. (c) 2007 Elsevier Inc. All rights reserved.Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Detroit, MI USAGATA Child & Adolescent Psychiat Dept, Ankara, TurkeyUniv Pittsburgh, Sch Med, Dept Psychiat, Western Psychiat Inst & Clin, Pittsburgh, PA USASINAPSE Inst, Div Neuropsychiat, Campinas, SP, BrazilUniversidade Federal de São Paulo, Dept Psychiat, Interdisciplinary Lab Neuroimaging & Cognit, LiNC, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychiat, Interdisciplinary Lab Neuroimaging & Cognit, LiNC, São Paulo, BrazilWeb of Scienc

Brain activation patterns during visual episodic memory processing among first-degree relatives of schizophrenia subjects

Episodic memory deficits are proposed as a potential intermediate phenotype of schizophrenia. We examined deficits in visual episodic memory and associated brain activation differences among early course schizophrenia (n = 22), first-degree relatives (n = 16) and healthy controls without personal or family history of psychotic disorders (n = 28).Study participants underwent functional magnetic resonance imaging on a 3. T scanner while performing visual episodic memory encoding and retrieval task. We examined in-scanner behavioral performance evaluating response time and accuracy of performance. Whole-brain BOLD response differences were analyzed using SPM5 correcting for multiple comparisons. There was an incremental increase in response time among the study groups (healthy controls \u3c first-degree relatives \u3c schizophrenia) with no differences in accuracy for encoding. Response time for retrieval was significantly increased in schizophrenia subjects compared to healthy controls with no difference in accuracy. Although there were no significant differences in BOLD responses for the encoding task, we noted increased BOLD response to retrieval in the prefrontal regions (Brodmann areas 9 and 8), thalamus and insula among the schizophrenia subjects compared to healthy controls, and first-degree relatives. Familial risk for schizophrenia may be associated with qualitatively similar but quantitatively milder abnormalities in visual episodic memory retrieval but not for encoding in the prefrontal cortex and thalamus. © 2012 Elsevier Inc