Neuropsychologische Endophänotypen der Schizophrenie : Neurokognitive und neuromotorische Normabweichungen bei wahrscheinlichen Anlageträgern für Schizophrenie

Einleitung: Die Schizophrenie ist eine klinisch heterogene und ätiologisch komplex determinierte psychiatrische Erkrankung. Die Identifikation von Endophänotypen – genetisch mit der Erkrankung assoziierten Normvarianten – kann eine Brücke zwischen dem Phänotyp und dem Genotyp schlagen, und so der weiteren molekulargenetischen Aufklärung der Erkrankung dienen. Neuropsychologische Störungen gehören zu den Kernmerkmalen der Schizophrenie, was sie potentiell zu geeigneten Kandidaten für die Suche nach endophänotypischen Markern für diese Erkrankung macht. In besonderem Maße informativ für die Suche nach Endophänotypen ist die Untersuchung sogenannter „more likely carrier“ (MLC) – eher wahrscheinlicher Anlageträger – bei denen aufgrund der familiären Position von einem hohen genetisch vermittelten Risiko ausgegangen werden kann. Nur eine einzige Studie untersuchte bislang neuropsychologische Leistungen bei wahrscheinlichen Anlageträgern für die Schizophrenie; die Stichprobe umfasste acht MLC.Methode: Es wurden 25 Patienten mit einer Schizophrenie vom paranoiden Typus (nach DSM-IV), 55 Eltern schizophren Erkrankter ohne eine Lebenszeitdiagnose einer psychotischen Störung, darunter 13 eher wahrscheinliche Anlageträger (MLC) und 11 weniger wahrscheinliche Anlageträger (LLC), sowie 80 Kontrollprobanden neuropsychologisch untersucht. Eingesetzt wurden Verfahren zur Erfassung von Aufmerksamkeits-, Gedächtnis- und Exekutivfunktionen sowie neuromotorischen Störungen.Ergebnisse: Die schizophrenen Patienten wiesen in allen neuropsychologischen Funktionsbereichen signifikante Beeinträchtigungen auf; der alle neurokognitiven Variablen zusammenfassende Globale Kognitive Index ergab eine signifikante Normabweichung von etwa zwei Standardabweichungen. Die biologischen Eltern schizophren Erkrankter zeigten ebenfalls bedeutsame – wenn auch im Vergleich zu den Patienten quantitativ geringere – neuropsychologische Defizite in allen erfassten Bereichen; bei ihnen fand sich im Globalen Kognitiven Index eine signifikante Normabweichung von etwa einer halben Standardabweichung. Besonders interessant waren die differentiellen Befunde zu den neuropsychologischen Leistungen der als eher wahrscheinliche (MLC) versus weniger wahrscheinliche (LLC) Anlageträger klassifizierten Elternteile. Während die MLC ausgeprägte Normabweichungen in allen drei erfassten kognitiven Funktionsbereichen – dem Gedächtnis, den Exekutivfunktionen und (ohne Ausschlüsse) auch der Aufmerksamkeit – sowie im neuromotorischen Bereich zeigten, wiesen die LLC ausschließlich im Bereich des Gedächtnisses signifikante Beeinträchtigungen auf. Der Globale Kognitive Index ergab bei den MLC eine signifikante Normabweichung von etwa einer Standardabweichung, bei den LLC war die Abweichung nicht bedeutsam. Der direkte Vergleich der beiden genetisch unterschiedlich belasteten Elterngruppen erbrachte besonders ausgeprägte und signifikante Leistungsdifferenzen im exekutiven Funktionsbereich. Die neuropsychologischen Defizite bei den Eltern schizophren Erkrankter zeigten sich als unabhängig von schizophrenierelevanten psychopathologischen Auffälligkeiten. Eine geschlechtsspezifische Analyse der Eltern-Daten ergab keine bedeutsamen geschlechtsgebundenen Effekte; Mütter und Väter schizophren Erkrankter wiesen vergleichbar stark ausgeprägte neuropsychologische Defizite auf.Schlussfolgerungen: Nach den Ergebnissen der Studie kommen in erster Linie Störungen der Exekutivfunktionen als mögliche neuropsychologische Endophänotypen der Schizophrenie, d.h. genetisch mit der Erkrankung assoziierte neuropsychologische Normvarianten, in Betracht

Novel Schizophrenia Risk Gene TCF4 Influences Verbal Learning and Memory Functioning in Schizophrenia Patients

Background: Recently, a role of the transcription factor 4 (TCF4) gene in schizophrenia has been reported in a large genome-wide association study. It has been hypothesized that TCF4 affects normal brain development and TCF4 has been related to different forms of neurodevelopmental disorders. Schizophrenia patients exhibit strong impairments of verbal declarative memory (VDM) functions. Thus, we hypothesized that the disease-associated C allele of the rs9960767 polymorphism of the TCF4 gene led to impaired VDM functioning in schizophrenia patients. Method: The TCF4 variant was genotyped in 401 schizophrenia patients. VDM functioning was measured using the Rey Auditory Verbal Learning Test (RAVLT). Results: Carriers of the C allele were less impaired in recognition compared to those carrying the AA genotype (13.76 vs. 13.06; p = 0.049). Moreover, a trend toward higher scores in patients with the risk allele was found for delayed recall (10.24 vs. 9.41; p = 0.088). The TCF4 genotype did not influence intelligence or RAVLT immediate recall or total verbal learning. Conclusion: VDM function is influenced by the TCF4 gene in schizophrenia patients. However, the elevated risk for schizophrenia is not conferred by TCF4-mediated VDM impairment. Copyright (C) 2011 S. Karger AG, Base

Antisaccade performance in patients with obsessive-compulsive disorder and unaffected relatives: further evidence for impaired response inhibition as a candidate endophenotype

Cognitive dysfunctions such as inhibitory deficits and visuospatial abnormalities are often found in patients with obsessive-compulsive disorder (OCD). Recent findings in unaffected relatives indicate that response inhibition and other neuropsychological functions may also constitute endophenotypes of OCD. In the present study, 30 OCD patients, 30 first-degree relatives, and 30 healthy control subjects were assessed using a comprehensive neuropsychological test battery. A subsample of 21 subjects of each group also performed an antisaccade task. The samples were matched according to age, gender, education, and verbal intelligence. The OCD patients and the unaffected OCD relatives showed increased antisaccade error rates compared with the healthy control group (p = 0.003, p = 0.028, respectively). Significantly prolonged antisaccade latencies as compared to prosaccade latencies were only found in the OCD patients compared with the healthy control group (p = 0.019). Only OCD patients but not the unaffected OCD relatives were impaired with regard to visuospatial functions, problem-solving, and processing speed. Antisaccade errors did not correlate with severity of OCD or depressive symptoms. This study confirms inhibitory deficits, as indicated by increased antisaccade error rates, as a candidate endophenotype of OCD. In agreement with previous findings from imaging studies, our data suggest that functional abnormalities in frontostriatal and parietal cortical regions form part of the vulnerability for OCD

Neurocognitive functioning in parents of schizophrenia patients: Attentional and executive performance vary with genetic loading

Neuropsychological deficits are candidate endophenotypes of schizophrenia which can assist to explain the neurocognitive impact of genetic risk variants. The identification of endophenotypes is often based on the familiality of these phenotypes. Several studies demonstrate neuropsychological deficits in unaffected biological relatives of schizophrenia patients without differentiating between genetic and non-genetic factors underlying these deficits. We assessed N=129 unaffected biological parents of schizophrenia patients, N=28 schizophrenia patients (paranoid subtype), and N=143 controls without a family history of schizophrenia with an extensive neuropsychological test battery. Direct comparison of N=22 parents with an ancestral history of schizophrenia (more likely carriers, MLC) and N=17 of their spouses without such a history (less likely carriers, LLC) allowed the separation of genetic and non-genetic aspects in cognition. Overall, parents showed significant deficits in neuropsychological tasks from all cognitive domains with medium effect sizes. Direct comparisons of MLC- and LLC-parents showed that attentional and executive tasks were most strongly affected by genetic loading. To conclude, unaffected parents of schizophrenia patients showed modest yet significant impairments in attention, memory, and executive functioning. In particular, attentional and executive impairments varied most strongly with genetic loading for schizophrenia, prioritising these dysfunctions for genotype-endophenotype analyses. (C) 2015 Elsevier Ireland Ltd. All rights reserved

The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) influences age at onset of obsessive-compulsive disorder

Neuropeptide S (NPS) is a novel central acting neuropeptide that modulates several brain functions. NPS has shown strong anxiolytic-like effects and interactions with other central transmitter systems, including serotonin and glutamate. A coding variation (Asn107Ile) of the NPS receptor gene (NPSR1) was associated with panic disorder and schizophrenia. Based on these encouraging findings, the present study aimed at exploring a potential role of NPSR1 in obsessive-compulsive disorder (OCD). A sample of 232 OCD patients was successfully genotyped for the NPSR1 Asn107Ile variant (rs324981). Age at onset was taken into account to address the heterogeneity of the OCD phenotype. The NPSR1 genotype significantly affected age at onset of the OCD patients, with a mean age at onset approximately 4 yr earlier in homozygous carriers of the low-functioning Asn107 variant compared to patients with at least one Ile107 variant (p=0.032). Case-control analyses with 308 healthy control subjects reveal a highly significant association of the Asn107 variant with early onset OCD (odds ratio=2.36, p=0.0004) while late onset OCD or the OCD group as a whole were unrelated to the NPSR1 genotype. Based on our association finding relating NPSR1 genotype to early onset OCD, we suggest a differential role of the NPS system in OCD. In particular, the early onset OCD subtype seems to be characterized by a genetically driven low NPS tone, which might affect other OCD-related transmitter systems, including the serotonin and glutamate systems. In agreement with preclinical research, we suggest that NPS may be a promising pharmacological candidate with anti-obsessional properties

The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) is associated with schizophrenia and modulates verbal memory and the acoustic startle response

Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies. A potential psychopharmacological effect of NPS on schizophrenia psychopathology was demonstrated by showing that NPS can block NMDA antagonist-induced deficits in prepulse inhibition. We therefore explored a potential role of the NPSR1 Asn107Ile variation in schizophrenia. A case-control sample of 778 schizophrenia patients and 713 healthy control subjects was successfully genotyped for NPSR1 Asn107Ile. Verbal declarative memory and acoustic startle response were measured in subsamples of the schizophrenia patients. The case-control comparison revealed that the low-functioning NPSR1 Asn107 variant was significantly associated with schizophrenia (OR 1.19, p=0.017). Moreover, specifically decreased verbal memory consolidation was found in homozygous Asn107 carriers while memory acquisition was unaffected by NPSR1 genotype. The schizophrenia patients carrying the Ile107 variant demonstrated significantly reduced startle amplitudes but unaffected prepulse inhibition and habituation. The present study confirms findings from rodent models demonstrating an effect of NPS on memory consolidation and startle response in schizophrenia patients. Based on these findings, we consider NPS as a promising target for antipsychotic drug development

5-HT3 receptor influences the washing phenotype and visual organization in obsessive-compulsive disorder supporting 5-HT3 receptor antagonists as novel treatment option

A role of the HTR3A-E genes in obsessive-compulsive disorder (OCD) can be expected based on promising effects of 5-HT3 receptor antagonists as adjunctive treatment of OCD. We therefore genotyped six common coding or promoter variants within the HTR3A-E genes in a case-control-sample consisting of N=236 OCD patients and N=310 control subjects and in N=58 parent-child-trios. Given the heterogeneous OCD phenotype, we also investigated OCD symptom dimensions and cognitive endophenotypes in subsamples. OCD patients scoring high for the washing subtype were significantly more likely to carry the c.256G-allele of the HTR3E variant rs7627615 (p=0.0001) as compared to OCD patients low for this symptom dimension. Visual organization was impaired in OCD patients and unaffected relatives as compared to healthy control subjects and carriers of the HTR3E c.256G/c.256G-genotype performed significantl

The German multi-centre study on smoking-related behavior-description of a population-based case-control study

Tobacco smoking is a major risk factor for most of the diseases leading in mortality. Nicotine dependence (ND), which sustains regular smoking, is now acknowledged to be under substantial genetic control with some environmental contribution. At present, however, genetic studies on ND are mostly conducted in populations that have been poorly characterized with regard to ND-related phenotypes for the simple reason that the respective populations were not primarily collected to study ND. The Germanmulti-centre study 'Genetics of Nicotine Dependence and Neurobiological Phenotypes', which is funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) as part of the Priority Program (Schwerpunktprogramm) SPP1226: 'Nicotine-Molecular and Physiological Effects in CNS', was intended to overcome some of these inherent problems of current genetic studies of ND. The multi-centre study is a population-based case-control study of smokers and never-smokers (n = 2396). The study was unique worldwide because it was the first large-scale genetic study specifically addressing ND with the collection of a wide range of environmental, psychosocial and neurobiological phenotypes. Study design and major population characteristics with emphasis on risk prediction of smoking status were presented in this paper