40 results on '"Leonhard Lennertz"'
Search Results
2. Neural correlates of working memory deficits and associations to response inhibition in obsessive compulsive disorder
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Stephan Heinzel, Christian Kaufmann, Rosa Grützmann, Robert Hummel, Julia Klawohn, Anja Riesel, Katharina Bey, Leonhard Lennertz, Michael Wagner, and Norbert Kathmann
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Computer applications to medicine. Medical informatics ,R858-859.7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Previous research in patients with obsessive-compulsive disorder (OCD) has indicated performance decrements in working memory (WM) and response inhibition. However, underlying neural mechanisms of WM deficits are not well understood to date, and empirical evidence for a proposed conceptual link to inhibition deficits is missing.We investigated WM performance in a numeric n-back task with four WM load conditions during functional Magnetic Resonance Imaging (fMRI) in 51 patients with OCD and 49 healthy control participants who were matched for age, sex, and education. Additionally, a stop signal task was performed outside the MRI scanner in a subsample.On the behavioral level, a significant WM load by group interaction was found for both accuracy (p
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- 2018
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3. Impaired Antisaccades in Obsessive-Compulsive Disorder: Evidence From Meta-Analysis and a Large Empirical Study
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Katharina Bey, Leonhard Lennertz, Rosa Grützmann, Stephan Heinzel, Christian Kaufmann, Julia Klawohn, Anja Riesel, Inga Meyhöfer, Ulrich Ettinger, Norbert Kathmann, and Michael Wagner
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obsessive-compulsive disorder ,OCD ,antisaccade ,endophenotype ,meta-analysis ,eye-tracking ,Psychiatry ,RC435-571 - Abstract
Increasing evidence indicates that patients with obsessive-compulsive disorder (OCD) exhibit alterations in fronto-striatal circuitry. Performance deficits in the antisaccade task would support this model, but results from previous small-scale studies have been inconclusive as either increased error rates, prolonged antisaccade latencies, both or neither have been reported in OCD patients. In order to address this issue, we investigated antisaccade performance in a large sample of OCD patients (n = 169) and matched control subjects (n = 183). As impaired antisaccade performance constitutes a potential endophenotype of OCD, unaffected first-degree relatives of OCD patients (n = 100) were assessed, as well. Furthermore, we conducted a quantitative meta-analysis to integrate our data with previous findings. In the empirical study, OCD patients exhibited significantly increased antisaccade latencies, intra-subject variability (ISV) of antisaccade latencies, and antisaccade error rates. The latter effect was driven by errors with express latency (80–130 ms), as patients did not differ significantly from controls with regards to regular errors (>130 ms). Notably, unaffected relatives of OCD patients showed elevated antisaccade express error rates and increased ISV of antisaccade latencies, as well. Antisaccade performance was not associated with state anxiety within groups. Among relatives, however, we observed a significant correlation between antisaccade error rate and harm avoidance. Medication status of OCD patients, symptom severity, depressive comorbidity, comorbid anxiety disorders and OCD symptom dimensions did not significantly affect antisaccade performance. Meta-analysis of 10 previous and the present empirical study yielded a medium-sized effect (SMD = 0.48, p < 0.001) for higher error rates in OCD patients, while the effect for latencies did not reach significance owing to strong heterogeneity (SMD = 0.51, p = 0.069). Our results support the assumption of impaired antisaccade performance in OCD, although effects sizes were only moderately large. Furthermore, we provide the first evidence that increased antisaccade express error rates and ISV of antisaccade latencies may constitute endophenotypes of OCD. Findings regarding these more detailed antisaccade parameters point to potentially underlying mechanisms, such as early pre-stimulus inhibition of the superior colliculus.
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- 2018
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4. Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture.
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Lea K Davis, Dongmei Yu, Clare L Keenan, Eric R Gamazon, Anuar I Konkashbaev, Eske M Derks, Benjamin M Neale, Jian Yang, S Hong Lee, Patrick Evans, Cathy L Barr, Laura Bellodi, Fortu Benarroch, Gabriel Bedoya Berrio, Oscar J Bienvenu, Michael H Bloch, Rianne M Blom, Ruth D Bruun, Cathy L Budman, Beatriz Camarena, Desmond Campbell, Carolina Cappi, Julio C Cardona Silgado, Danielle C Cath, Maria C Cavallini, Denise A Chavira, Sylvain Chouinard, David V Conti, Edwin H Cook, Vladimir Coric, Bernadette A Cullen, Dieter Deforce, Richard Delorme, Yves Dion, Christopher K Edlund, Karin Egberts, Peter Falkai, Thomas V Fernandez, Patience J Gallagher, Helena Garrido, Daniel Geller, Simon L Girard, Hans J Grabe, Marco A Grados, Benjamin D Greenberg, Varda Gross-Tsur, Stephen Haddad, Gary A Heiman, Sian M J Hemmings, Ana G Hounie, Cornelia Illmann, Joseph Jankovic, Michael A Jenike, James L Kennedy, Robert A King, Barbara Kremeyer, Roger Kurlan, Nuria Lanzagorta, Marion Leboyer, James F Leckman, Leonhard Lennertz, Chunyu Liu, Christine Lochner, Thomas L Lowe, Fabio Macciardi, James T McCracken, Lauren M McGrath, Sandra C Mesa Restrepo, Rainald Moessner, Jubel Morgan, Heike Muller, Dennis L Murphy, Allan L Naarden, William Cornejo Ochoa, Roel A Ophoff, Lisa Osiecki, Andrew J Pakstis, Michele T Pato, Carlos N Pato, John Piacentini, Christopher Pittenger, Yehuda Pollak, Scott L Rauch, Tobias J Renner, Victor I Reus, Margaret A Richter, Mark A Riddle, Mary M Robertson, Roxana Romero, Maria C Rosàrio, David Rosenberg, Guy A Rouleau, Stephan Ruhrmann, Andres Ruiz-Linares, Aline S Sampaio, Jack Samuels, Paul Sandor, Brooke Sheppard, Harvey S Singer, Jan H Smit, Dan J Stein, E Strengman, Jay A Tischfield, Ana V Valencia Duarte, Homero Vallada, Filip Van Nieuwerburgh, Jeremy Veenstra-Vanderweele, Susanne Walitza, Ying Wang, Jens R Wendland, Herman G M Westenberg, Yin Yao Shugart, Euripedes C Miguel, William McMahon, Michael Wagner, Humberto Nicolini, Danielle Posthuma, Gregory L Hanna, Peter Heutink, Damiaan Denys, Paul D Arnold, Ben A Oostra, Gerald Nestadt, Nelson B Freimer, David L Pauls, Naomi R Wray, S Evelyn Stewart, Carol A Mathews, James A Knowles, Nancy J Cox, and Jeremiah M Scharf
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Genetics ,QH426-470 - Abstract
The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
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- 2013
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5. Characterization of SLITRK1 variation in obsessive-compulsive disorder.
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Uzoezi Ozomaro, Guiqing Cai, Yuji Kajiwara, Seungtai Yoon, Vladimir Makarov, Richard Delorme, Catalina Betancur, Stephan Ruhrmann, Peter Falkai, Hans Jörgen Grabe, Wolfgang Maier, Michael Wagner, Leonhard Lennertz, Rainald Moessner, Dennis L Murphy, Joseph D Buxbaum, Stephan Züchner, and Dorothy E Grice
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Medicine ,Science - Abstract
Obsessive compulsive disorder (OCD) is a syndrome characterized by recurrent and intrusive thoughts and ritualistic behaviors or mental acts that a person feels compelled to perform. Twin studies, family studies, and segregation analyses provide compelling evidence that OCD has a strong genetic component. The SLITRK1 gene encodes a developmentally regulated stimulator of neurite outgrowth and previous studies have implicated rare variants in this gene in disorders in the OC spectrum, specifically Tourette syndrome (TS) and trichotillomania (TTM). The objective of the current study was to evaluate rare genetic variation in SLITRK1 in risk for OCD and to functionally characterize associated coding variants. We sequenced SLITRK1 coding exons in 381 individuals with OCD as well as in 356 control samples and identified three novel variants in seven individuals. We found that the combined mutation load in OCD relative to controls was significant (p = 0.036). We identified a missense N400I change in an individual with OCD, which was not found in more than 1000 control samples (P
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- 2013
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6. Spatial working memory performance in people with obsessive–compulsive disorder, their unaffected first-degree relatives and healthy controls
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Christian Kaufmann, Leonhard Lennertz, Stephan Heinzel, Norbert Kathmann, Rosa Grützmann, Anja Riesel, Julia Klawohn, Michael Wagner, and Katharina Bey
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Short Report ,risk assessment ,Spatial memory ,behavioral disciplines and activities ,Obsessive–compulsive disorder ,humanities ,first-degree relatives ,endophenotype ,Psychiatry and Mental health ,ddc:150 ,Obsessive compulsive ,mental disorders ,First-degree relatives ,Psychology ,100 Philosophie und Psychologie::150 Psychologie::150 Psychologie ,spatial working memory ,Clinical psychology - Abstract
Summary Studies have shown that people with obsessive–compulsive disorder (OCD) have impairments in spatial working memory (SWM) performance. However, it remains unclear whether this deficit represents a cognitive endophenotype preceding symptoms or a correlate of OCD. We investigated SWM in 69 people with OCD, 77 unaffected first-degree relatives of people with OCD and 106 healthy control participants. Taking age effects into account, SWM performance was best in healthy controls, intermediate in relatives and worst in OCD participants. However, since performance did not differ significantly between healthy controls and relatives, our study does not fully support SWM performance as a core cognitive endophenotype of OCD.
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- 2021
7. Author response for 'The polygenic risk for obsessive‐compulsive disorder is associated with the personality trait harm avoidance'
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Michael von Wagner, Leonie Weinhold, Alfredo Ramirez, Norbert Kathmann, Leonhard Lennertz, Julia Klawohn, Stephan Heinzel, Rosa Grützmann, Anja Riesel, Christian Kaufmann, Katharina Bey, and Matthias Schmid
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Obsessive compulsive ,media_common.quotation_subject ,Trait ,medicine ,Harm avoidance ,Personality ,Polygenic risk score ,Psychology ,medicine.disease ,media_common ,Clinical psychology - Published
- 2020
8. Impaired planning in patients with obsessive-compulsive disorder and unaffected first-degree relatives: Evidence for a cognitive endophenotype
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Rosa Grützmann, Michael Wagner, Anja Riesel, Julia Klawohn, Leonhard Lennertz, Norbert Kathmann, Stephan Heinzel, Christian Kaufmann, and Katharina Bey
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Adult ,Male ,Obsessive-Compulsive Disorder ,complications [Cognition Disorders] ,Endophenotypes ,psychology [Cognition Disorders] ,Affect (psychology) ,behavioral disciplines and activities ,complications [Obsessive-Compulsive Disorder] ,Executive Function ,03 medical and health sciences ,Cognition ,0302 clinical medicine ,ddc:150 ,Obsessive compulsive ,mental disorders ,medicine ,Humans ,In patient ,First-degree relatives ,Problem Solving ,Family Health ,psychology [Obsessive-Compulsive Disorder] ,Small sample ,Middle Aged ,medicine.disease ,Comorbidity ,030227 psychiatry ,Psychiatry and Mental health ,Clinical Psychology ,Endophenotype ,Female ,Cognition Disorders ,Psychology ,030217 neurology & neurosurgery ,Clinical psychology - Abstract
Patients with obsessive-compulsive disorder (OCD) show deficient planning capacity in the Tower of London (TOL) problem solving task. Preliminary evidence for similar deficits in unaffected first-degree relatives suggests that impaired planning may constitute an endophenotype of OCD. However, results on this issue are inconsistent, possibly owing to small sample sizes and variability in problem structure across TOL tasks. Here, we adopted a computerized version of the TOL task featuring a 2 × 2 factorial design (high/low search depth × full/partial tower goal state) and examined a well-characterized sample of n = 72 OCD patients, n = 76 unaffected first-degree relatives and n = 102 healthy comparison subjects. Both OCD patients and relatives exhibited significantly less accurate problem solving than controls. Search depth, goal hierarchy, or the number of minimum moves did not moderate these group differences. Medication, OCD symptoms, and depressive comorbidity did not affect TOL performance in patients, suggesting a state-independent effect. In conclusion, we found that OCD patients as well as unaffected first-degree relatives show deficient TOL performance across a range of task conditions, strongly supporting the role of impaired planning as an endophenotype of OCD, and contributing to the growing evidence for fronto-striatal dysfunctions in OCD.
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- 2018
9. Schizotypy and smooth pursuit eye movements as potential endophenotypes of obsessive-compulsive disorder
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Leonhard Lennertz, Norbert Kathmann, Katharina Bey, Michael Wagner, Stephan Heinzel, Anja Riesel, Ulrich Ettinger, Christian Kaufmann, Julia Klawohn, Inga Meyhöfer, and Rosa Grützmann
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Adult ,Male ,Obsessive-Compulsive Disorder ,Endophenotypes ,Schizotypy ,behavioral disciplines and activities ,Smooth pursuit ,Schizotypal Personality Disorder ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,physiology [Pursuit, Smooth] ,Obsessive compulsive ,mental disorders ,Basal ganglia ,Humans ,Medicine ,Family ,Pharmacology (medical) ,ddc:610 ,Young adult ,Big Five personality traits ,Biological Psychiatry ,business.industry ,physiopathology [Obsessive-Compulsive Disorder] ,General Medicine ,Middle Aged ,physiopathology [Schizotypal Personality Disorder] ,medicine.disease ,Pursuit, Smooth ,humanities ,030227 psychiatry ,Psychiatry and Mental health ,Schizophrenia ,Endophenotype ,Female ,business ,030217 neurology & neurosurgery ,Clinical psychology - Abstract
Patients with obsessive-compulsive disorder (OCD) show dysfunctions of the fronto-striatal circuitry, which imply corresponding oculomotor deficits including smooth pursuit eye movements (SPEM). However, evidence for a deficit in SPEM is inconclusive, with some studies reporting reduced velocity gain while others did not find any SPEM dysfunctions in OCD patients. Interestingly, psychosis-like traits have repeatedly been linked to both OCD and impaired SPEM. Here, we examined a large sample of n = 168 patients with OCD, n = 93 unaffected first-degree relatives and n = 171 healthy control subjects to investigate whether elevated levels of schizotypy and SPEM deficits represent potential endophenotypes of OCD. We applied a SPEM task with high demands on predictive pursuit that is more sensitive to assess executive dysfunctions than a standard task with continuous visual feedback, as episodes of target blanking put increased demands on basal ganglia and prefrontal involvement. Additionally, we examined the relation between schizotypy and SPEM performance in OCD patients and their relatives. Results indicate that OCD patients and unaffected relatives do not show deficient performance in either standard or predictive SPEM. Yet, both patients and relatives exhibited elevated levels of schizotypy, and schizotypy was significantly correlated with velocity gain during standard trials in unmedicated and depression-free OCD patients. These findings highlight the role of schizotypy as a candidate endophenotype of OCD and add to the growing evidence for predisposing personality traits in OCD. Furthermore, intact gain may represent a key characteristic that distinguishes the OCD and schizophrenia patient populations.
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- 2018
10. Volitional saccade performance in a large sample of patients with obsessive-compulsive disorder and unaffected first-degree relatives
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Inga Meyhöfer, Rosa Grützmann, Leonhard Lennertz, Christian Kaufmann, Stephan Heinzel, Lisa Kloft, Norbert Kathmann, Julia Klawohn, Michael Wagner, Katharina Bey, and Anja Riesel
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Volition ,Adult ,Male ,Obsessive-Compulsive Disorder ,medicine.medical_specialty ,Endophenotypes ,Cognitive Neuroscience ,Experimental and Cognitive Psychology ,physiology [Volition] ,Audiology ,behavioral disciplines and activities ,050105 experimental psychology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Developmental Neuroscience ,Obsessive compulsive ,mental disorders ,Saccades ,medicine ,Humans ,Family ,0501 psychology and cognitive sciences ,ddc:610 ,First-degree relatives ,Family history ,Psychiatry ,Biological Psychiatry ,Volitional control ,Endocrine and Autonomic Systems ,physiology [Saccades] ,General Neuroscience ,05 social sciences ,physiopathology [Obsessive-Compulsive Disorder] ,Middle Aged ,medicine.disease ,Comorbidity ,Large sample ,Neuropsychology and Physiological Psychology ,Neurology ,Endophenotype ,Saccade ,Female ,Psychology ,030217 neurology & neurosurgery - Abstract
Recent evidence indicates that patients with obsessive-compulsive disorder (OCD) as well as their unaffected first-degree relatives show deficits in the volitional control of saccades, suggesting that volitional saccade performance may constitute an endophenotype of OCD. Here, we aimed to replicate and extend these findings in a large, independent sample. One hundred and fifteen patients with OCD, 103 healthy comparison subjects without a family history of OCD, and 31 unaffected first-degree relatives of OCD patients were examined using structured clinical interviews and performed a volitional saccade task as well as a prosaccade task. In contrast to previous reports, neither patients nor relatives showed impairments in the performance of volitional saccades compared to healthy controls. Notably, medicated patients did not differ from nonmedicated patients, and there was no effect of depressive comorbidity. Additional analyses investigating correlations between saccade performance and OCD symptom dimensions yielded no significant associations. In conclusion, the present results do not support the notion that volitional saccade execution constitutes an endophenotype of OCD. Possible explanations for inconsistencies with previous studies are discussed.
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- 2017
11. Error-related brain activity as a transdiagnostic endophenotype for obsessive-compulsive disorder, anxiety and substance use disorder
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Norbert Kathmann, Katharina Bey, Leonhard Lennertz, Julia Klawohn, Anja Riesel, Stephan Heinzel, Christian Kaufmann, Michael Wagner, and Rosa Grützmann
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Male ,Obsessive-Compulsive Disorder ,error-related negativity ,0302 clinical medicine ,Attention ,error-realted negativity ,Family history ,Applied Psychology ,Depression (differential diagnoses) ,substance use disorder ,unaffected first-degree relatives ,05 social sciences ,Electroencephalography ,Middle Aged ,humanities ,Substance abuse ,endophenotype ,Psychiatry and Mental health ,medicine.anatomical_structure ,transdiagnostic risk marker ,depression ,Anxiety ,Female ,medicine.symptom ,Clinical psychology ,Psychopathology ,Adult ,Endophenotypes ,Substance-Related Disorders ,Contingent Negative Variation ,behavioral disciplines and activities ,050105 experimental psychology ,Error-related negativity ,03 medical and health sciences ,anxiety disorders ,mental disorders ,medicine ,Humans ,0501 psychology and cognitive sciences ,family study ,ddc:610 ,100 Philosophie und Psychologie::150 Psychologie::150 Psychologie ,Anterior cingulate cortex ,business.industry ,obssessive-compulsive disorder ,Original Articles ,medicine.disease ,Endophenotype ,business ,030217 neurology & neurosurgery - Abstract
BackgroundIncreased neural error-signals have been observed in obsessive-compulsive disorder (OCD), anxiety disorders, and inconsistently in depression. Reduced neural error-signals have been observed in substance use disorders (SUD). Thus, alterations in error-monitoring are proposed as a transdiagnostic endophenotype. To strengthen this notion, data from unaffected individuals with a family history for the respective disorders are needed.MethodsThe error-related negativity (ERN) as a neural indicator of error-monitoring was measured during a flanker task from 117 OCD patients, 50 unaffected first-degree relatives of OCD patients, and 130 healthy comparison participants. Family history information indicated, that 76 healthy controls were free of a family history for psychopathology, whereas the remaining had first-degree relatives with depression (n = 28), anxiety (n = 27), and/or SUD (n = 27).ResultsIncreased ERN amplitudes were found in OCD patients and unaffected first-degree relatives of OCD patients. In addition, unaffected first-degree relatives of individuals with anxiety disorders were also characterized by increased ERN amplitudes, whereas relatives of individuals with SUD showed reduced amplitudes.ConclusionsAlterations in neural error-signals in unaffected first-degree relatives with a family history of OCD, anxiety, or SUD support the utility of the ERN as a transdiagnostic endophenotype. Reduced neural error-signals may indicate vulnerability for under-controlled behavior and risk for substance use, whereas a harm- or error-avoidant response style and vulnerability for OCD and anxiety appears to be associated with increased ERN. This adds to findings suggesting a common neurobiological substrate across psychiatric disorders involving the anterior cingulate cortex and deficits in cognitive control.
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- 2019
12. The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia
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Laura Ferraro, Michael John Owen, Tracey L. Petryshen, Franziska Degenhardt, Derek W. Morris, Alexander Richards, Aura Frizzati, Ingrid Agartz, Leonhard Lennertz, Ingrid Melle, Fabian Streit, Jim van Os, Bart P. F. Rutten, Bettina Konte, Valentina Escott-Price, Annette M. Hartmann, Håkan Nyman, Ole A. Andreassen, Jana Strohmaier, Diego Quattrone, John Hubert, Gary Donohoe, Sophie E. Legge, Roel A. Ophoff, Loes M. Olde Loohuis, Amy Lynham, Dan Rujescu, Gabriëlla A.M. Blokland, James T.R. Walters, Jeanne E. Savage, Peter Holmans, Craig Morgan, Erik G. Jönsson, Robin M. Murray, Neeltje E.M. van Haren, Kjetil Sundet, Charlotte Gayer-Anderson, Antonio F. Pardiñas, Donna Cosgrove, Michael Wagner, Marcella Rietschel, Michael Conlon O'Donovan, Aiden Corvin, Patrick F. Sullivan, Thomas Espeseth, Ina Giegling, Katherine E. Tansey, Srdjan Djurovic, Child and Adolescent Psychiatry / Psychology, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: Hersen en Zenuw Centrum (3), MUMC+: MA Psychiatrie (3), RS: MHeNs - R3 - Neuroscience, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Richards, Alexander L, Pardiñas, Antonio F, Frizzati, Aura, Tansey, Katherine E, Lynham, Amy J, Holmans, Peter, Legge, Sophie E, Savage, Jeanne E, Agartz, Ingrid, Andreassen, Ole A, Blokland, Gabriella A M, Corvin, Aiden, Cosgrove, Donna, Degenhardt, Franziska, Djurovic, Srdjan, Espeseth, Thoma, Ferraro, Laura, Gayer-Anderson, Charlotte, Giegling, Ina, van Haren, Neeltje E, Hartmann, Annette M, Hubert, John J, Jönsson, Erik G, Konte, Bettina, Lennertz, Leonhard, Olde Loohuis, Loes M, Melle, Ingrid, Morgan, Craig, Morris, Derek W, Murray, Robin M, Nyman, Håkan, Ophoff, Roel A, van Os, Jim, Petryshen, Tracey L, Quattrone, Diego, Rietschel, Marcella, Rujescu, Dan, Rutten, Bart P F, Streit, Fabian, Strohmaier, Jana, Sullivan, Patrick F, Sundet, Kjetil, Wagner, Michael, Escott-Price, Valentina, Owen, Michael J, Donohoe, Gary, O’Donovan, Michael C, and Walters, James T R
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Multifactorial Inheritance ,Bipolar Disorder ,Datasets as Topic ,INTELLIGENCE ,Genome-wide association study ,0302 clinical medicine ,genetics [Schizophrenia] ,education.field_of_study ,HERITABILITY ,COMMON VARIANTS ,Cognition ,bioinformatics ,intelligence ,psychiatry ,ABILITY ,Psychiatry and Mental health ,Schizophrenia ,Major depressive disorder ,Educational Status ,psychiatry, genomics, intelligence, bioinformatics ,Clinical psychology ,Population ,genetics [Psychotic Disorders] ,behavioral disciplines and activities ,03 medical and health sciences ,mental disorders ,genomics ,medicine ,Humans ,Bipolar disorder ,ddc:610 ,GENOME-WIDE ASSOCIATION ,education ,Settore MED/25 - Psichiatria ,METAANALYSIS ,Genetic association ,Depressive Disorder, Major ,ENDOPHENOTYPES ,business.industry ,MEMORY ,CONSORTIUM ,genetics [Depressive Disorder, Major] ,PERFORMANCE ,medicine.disease ,030227 psychiatry ,Psychotic Disorders ,genetics [Intelligence] ,Endophenotype ,business ,030217 neurology & neurosurgery ,genetics [Bipolar Disorder] ,Regular Articles ,Genome-Wide Association Study - Abstract
Background Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. Methods We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. Results PRS for both population IQ (P = 4.39 × 10–28) and EA (P = 1.27 × 10–26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. Conclusions Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.
- Published
- 2019
13. M62 THE POLYGENIC RISK FOR OBSESSIVE-COMPULSIVE DISORDER IS ASSOCIATED WITH HARM AVOIDANCE IN A SAMPLE OF OCD PATIENTS, UNAFFECTED RELATIVES AND CONTROLS
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Rosa Grützmann, Katharina Bey, Leonhard Lennertz, Anja Riesel, Michael Wagner, Alfredo Ramirez, Leonie Weinhold, Norbert Kathmann, Matthias Schmid, Stephan Heinzel, Julia Klawohn, and Christian Kaufmann
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Pharmacology ,medicine.medical_specialty ,business.industry ,Sample (statistics) ,medicine.disease ,Psychiatry and Mental health ,Neurology ,Obsessive compulsive ,medicine ,Harm avoidance ,Pharmacology (medical) ,Polygenic risk score ,Neurology (clinical) ,Psychiatry ,business ,Biological Psychiatry - Published
- 2019
14. Smaller than expected cognitive deficits in schizophrenia patients from the population-representative ABC catchment cohort
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Leonhard Lennertz, Heinz Häfner, Michael Wagner, Regina Kronacher, Wolfgang Maier, Svenja Schulze-Rauschenbach, and Wolfram an der Heiden
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Adult ,Male ,medicine.medical_specialty ,Population ,Neuropsychological Tests ,Cohort Studies ,Executive Function ,03 medical and health sciences ,0302 clinical medicine ,Catchment Area, Health ,Memory ,complications [Schizophrenia] ,medicine ,Humans ,Attention ,Pharmacology (medical) ,ddc:610 ,Neuropsychological assessment ,Sex Distribution ,education ,Psychiatry ,physiology [Memory] ,Biological Psychiatry ,Aged ,Psychiatric Status Rating Scales ,education.field_of_study ,medicine.diagnostic_test ,Neuropsychology ,etiology [Cognition Disorders] ,Cognition ,General Medicine ,Neuropsychological test ,Middle Aged ,Executive functions ,030227 psychiatry ,physiology [Executive Function] ,Psychiatry and Mental health ,physiology [Attention] ,Cohort ,Schizophrenia ,Female ,Schizophrenic Psychology ,Verbal memory ,Cognition Disorders ,Psychology ,030217 neurology & neurosurgery ,Clinical psychology - Abstract
Most neuropsychological studies on schizophrenia suffer from sample selection bias, with male and chronic patients being overrepresented. This probably leads to an overestimation of cognitive impairments. The present study aimed to provide a less biased estimate of cognitive functions in schizophrenia using a population-representative catchment area sample. Schizophrenia patients (N = 89) from the prospective Mannheim ABC cohort were assessed 14 years after disease onset and first diagnosis, using a comprehensive neuropsychological test battery. A healthy control group (N = 90) was carefully matched according to age, gender, and geographic region (city, rural surrounds). The present sample was representative for the initial ABC cohort. In the comprehensive neuropsychological assessment, the schizophrenia patients were only moderately impaired as compared to the healthy control group (d = 0.56 for a general cognitive index, d = 0.42 for verbal memory, d = 0.61 for executive functions, d = 0.69 for attention). Only 33 % of the schizophrenia patients scored one standard deviation unit below the healthy control group in the general cognitive index. Neuropsychological performance did not correlate with measures of the clinical course including age at onset, number of hospital admissions, and time in paid work. Thus, in this population-representative sample of schizophrenia patients, neuropsychological deficits were less pronounced than expected from meta-analyses. In agreement with other epidemiological studies, this suggests a less devastating picture of cognition in schizophrenia.
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- 2015
15. Harm avoidance and childhood adversities in patients with obsessive-compulsive disorder and their unaffected first-degree relatives
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Leonhard Lennertz, Julia Klawohn, Stephan Heinzel, Christian Kaufmann, Rosa Grützmann, Norbert Kathmann, Michael Wagner, Katharina Bey, and Anja Riesel
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Adult ,Male ,Obsessive-Compulsive Disorder ,medicine.medical_specialty ,Personality Inventory ,Endophenotypes ,media_common.quotation_subject ,psychology [Fear] ,behavioral disciplines and activities ,Life Change Events ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,psychology [Family] ,Harm Reduction ,Surveys and Questionnaires ,mental disorders ,medicine ,Personality ,Humans ,Family ,In patient ,ddc:610 ,First-degree relatives ,Psychiatry ,Child ,media_common ,Family Health ,psychology [Obsessive-Compulsive Disorder] ,Psychiatric Status Rating Scales ,psychology [Stress, Psychological] ,Fear ,Middle Aged ,medicine.disease ,030227 psychiatry ,Psychiatry and Mental health ,Endophenotype ,Trait ,Etiology ,Harm avoidance ,Temperament and Character Inventory ,Female ,Psychology ,Stress, Psychological ,030217 neurology & neurosurgery - Abstract
Objective The etiology of obsessive–compulsive disorder (OCD) is assumed to involve interactions between genetically determined vulnerability factors and significant environmental features. Here, we aim to investigate how the personality trait harm avoidance and the experience of childhood adversities contribute to OCD. Method A total of 169 patients with OCD, 157 healthy comparison subjects, and 57 unaffected first-degree relatives of patients with OCD participated in the study. Harm avoidance was assessed using the Temperament and Character Inventory, and the severity of childhood adversities was measured with the Childhood Trauma Questionnaire. Results Both patients with OCD and relatives showed elevated levels of harm avoidance compared to controls. Furthermore, patients exhibited significantly higher scores than relatives. This linear pattern was observed throughout all subscales of harm avoidance, and remained stable after controlling for the severity of depressive and obsessive–compulsive symptoms. With regard to childhood adversities, patients with OCD reported higher levels than relatives and controls. Conclusion Our results provide further evidence for a diathesis-stress model of OCD. While patients and unaffected relatives share elevated levels of harm avoidance, supporting the role of harm avoidance as an endophenotype of OCD, a heightened severity of childhood adversity was only observed in patients. The assumed biological underpinnings of these findings are discussed.
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- 2017
16. Serotonintransportergen und Stressreagibilität bei unipolarer Depression
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Vera Guttenthaler, Leonhard Lennertz, A Aller, Susanne Höfels, U. Pfeiffer, Sibylle G. Schwab, Hanne Welper, and A. Zobel
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Gynecology ,Psychiatry and Mental health ,medicine.medical_specialty ,Neurology ,business.industry ,medicine ,Psychosomatic medicine ,Neurology (clinical) ,General Medicine ,business ,Depression (differential diagnoses) - Abstract
Hintergrund Ein Langenpolymorphismus in der Promoterregion des Serotonintransportergens (5-HTTLPR) wird sowohl mit der Depression als auch mit der Stressreagibilitat in Verbindung gebracht. Gleichzeitig gilt eine Dysregulation des Hypothalamic-pituitary-adrenal(HPA)-Systems als Endophanotypkandidat der Depression. Ziel der vorliegenden Studie war es, einen moglichen Einfluss des 5-HTTLPR-Genotyps auf die HPA-Systemaktivitat bei akut depressiv erkrankten Patienten zu untersuchen und Aussagen hinsichtlich einer moglichen Gen-Endophanotypen-Interaktion zu treffen.
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- 2013
17. Genome-wide association study of obsessive-compulsive disorder
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Helena Garrido, Richard O'Brien, Michael H. Bloch, David L. Pauls, M. Van Der Brug, Anna Tikhomirov, Andrew B. Singleton, Susanne Walitza, Benjamin M. Neale, Patrick Evans, Rianne M. Blom, Mina Ryten, James L. Kennedy, Christopher Pittenger, C. Illman, Amin Azzam, Stephen A. Haddad, Gregory L. Hanna, Michele T. Pato, D. Rosenberg, Maurizio Turiel, Stephan Ruhrmann, Peter Falkai, Nuria Lanzagorta, Richard Delorme, D. G. Hernandez, Leonhard Lennertz, Abby J. Fyer, M Conceição do Rosário, Euripedes Constantino Miguel, John Hardy, Carlos N. Pato, Francesca Frau, Hans-Jörgen Grabe, Daniele Cusi, Alan B. Zonderman, Dieter Deforce, Peter Heutink, Brooke Sheppard, Jacquelyn Crane, Dongmei Yu, Danielle C. Cath, Rainald Moessner, Nancy J. Cox, Shaun Purcell, James A. Knowles, Daniel B. Mirel, Aline S. Sampaio, D. L. Murphy, R. Johnson, Jens R. Wendland, David V. Conti, Carolina Cappi, Paula Umaña, Marco A. Grados, Dan J. Stein, J. R. Gibbs, Humberto Nicolini, Anna Pluzhnikov, Denise A. Chavira, F. Van Nieuwerburgh, Valsamma Eapen, Lisa Osiecki, Christine Lochner, Juan C. Troncoso, Jeremy Veenstra-VanderWeele, Mark A. Riddle, Michael Wagner, Jeremiah M. Scharf, Beatriz Camarena, Edwin H. Cook, Ana Gabriela Hounie, Daniah Trabzuni, Donald W. Black, Scott L. Rauch, Marion Leboyer, Andrew Crenshaw, S. E. Stewart, Roel A. Ophoff, Dianne M. Hezel, Damiaan Denys, Gerald Nestadt, Melissa Parkin, Karin Egberts, Colin Smith, Anuar Konkashbaev, Danielle Posthuma, Vladimir Coric, James F. Leckman, Eric Strengman, Jack Samuels, Tobias J. Renner, Michael E. Weale, L. Ferrucci, Mark R. Cookson, Laura Bellodi, Oscar J. Bienvenu, C. Mayerfeld, Christopher K. Edlund, Youfa Wang, Robert Walker, Dan L. Longo, Maria Cristina Cavallini, James T. McCracken, Jesen Fagerness, H. R. Zielke, Homero Vallada, Chunyu Liu, Bernadette Cullen, Carol A. Mathews, Sian M. J. Hemmings, Allissa Dillman, E. Voyiaziakis, Fabio Macciardi, Eduardo Fournier, Benjamin D. Greenberg, Eric R. Gamazon, S. Arepalli, Margaret A. Richter, Bryan J. Traynor, Michael A. Jenike, J.H. Smit, M. A. Nalls, Lauren M. McGrath, Paul D. Arnold, H.G.M. Westenberg, W. Maier, Other departments, ANS - Amsterdam Neuroscience, Adult Psychiatry, Functional Genomics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Netherlands Institute for Neuroscience (NIN), Human genetics, Psychiatry, NCA - Brain mechanisms in health and disease, and NCA - Neurobiology of mental health
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Parents ,Obsessive-Compulsive Disorder ,OCD COLLABORATIVE GENETICS ,SLC1A1 ,Genome-wide association study ,genomic ,0302 clinical medicine ,Polymorphism (computer science) ,TRANSPORTER GENE ,GWAS ,SNPS ,Genetics ,QUANTITATIVE TRAIT LOCI ,0303 health sciences ,biology ,Frontal Lobe ,obsessive-compulsive disorder ,Psychiatry and Mental health ,EXPRESSION ,Quantitative Trait Loci ,TWIN ,Nerve Tissue Proteins ,Single-nucleotide polymorphism ,Quantitative trait locus ,Polymorphism, Single Nucleotide ,Article ,White People ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,SDG 17 - Partnerships for the Goals ,DLGAP ,Genetic variation ,mental disorders ,LINKAGE ,Humans ,SNP ,Genetic Predisposition to Disease ,Molecular Biology ,FAMILY-BASED ASSOCIATION ,030304 developmental biology ,Biology and Life Sciences ,neurodevelopmental disorder ,SAP90-PSD95 Associated Proteins ,Case-Control Studies ,REPLICATION ,Expression quantitative trait loci ,biology.protein ,genetic ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469 410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P = 2.49 x 10(-6) and P = 3.44 x 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value = 3.84 x 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 x 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P < 0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P = 0.001) was observed within the top-ranked SNPs (P < 0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.
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- 2013
18. The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) influences age at onset of obsessive-compulsive disorder
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Vera Guttenthaler, Leonhard Lennertz, Peter Falkai, Friederike Rampacher, Petra Franke, Joachim Klosterkötter, Stephan Ruhrmann, Rainald Mössner, Wolfgang Maier, Hans J. Grabe, Ralf Pukrop, Svenja Schulze-Rauschenbach, and Michael Wagner
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Adult ,Male ,Heterozygote ,Obsessive-Compulsive Disorder ,medicine.medical_specialty ,Late onset ,Polymorphism, Single Nucleotide ,behavioral disciplines and activities ,Receptors, G-Protein-Coupled ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Gene Frequency ,Risk Factors ,Germany ,Internal medicine ,mental disorders ,Neuropeptide S ,Genotype ,Odds Ratio ,medicine ,Humans ,Genetic Predisposition to Disease ,Pharmacology (medical) ,Age of Onset ,Neuropeptide S receptor ,Genetic Association Studies ,Pharmacology ,Chi-Square Distribution ,Panic disorder ,Homozygote ,Odds ratio ,Middle Aged ,medicine.disease ,030227 psychiatry ,Psychiatry and Mental health ,Phenotype ,Endocrinology ,Schizophrenia ,Case-Control Studies ,Female ,Age of onset ,Psychology ,030217 neurology & neurosurgery - Abstract
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.
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- 2013
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19. Association of amygdala volumes with cortisol secretion in unipolar depressed patients
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Leonhard Lennertz, Wolfgang Block, Astrid Zobel, Frank Jessen, Anna Christine Belloche, Lukas Scheef, Michael Wagner, Rainald Mössner, S. G. Schwab, Anna Schuhmacher, Wolfgang Maier, Susanne Höfels, U. Pfeiffer, and Hanne Welper
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Adult ,Male ,Cortisol secretion ,endocrine system ,medicine.medical_specialty ,Adolescent ,Hydrocortisone ,Neuroscience (miscellaneous) ,Hippocampus ,Adrenocorticotropic hormone ,Amygdala ,Dexamethasone ,Young Adult ,Corticotropin-releasing hormone ,Adrenocorticotropic Hormone ,Internal medicine ,Image Processing, Computer-Assisted ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Radionuclide Imaging ,Psychiatric Status Rating Scales ,Analysis of Variance ,Depressive Disorder ,Hamilton Rating Scale for Depression ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Psychiatry and Mental health ,Glucocorticoid secretion ,Endocrinology ,medicine.anatomical_structure ,nervous system ,Area Under Curve ,Major depressive disorder ,Female ,Psychology ,hormones, hormone substitutes, and hormone antagonists - Abstract
Major depressive disorder (MDD) is accompanied by morphological changes of brain structures which are of great importance in the neural circuitry mediating depression like the hippocampus and the amygdala. Hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system resulting in enhanced glucocorticoid secretion can often be observed during depression and has been thought to play an important role in inducing these morphological changes. We used magnetic resonance imaging to investigate alterations of amygdala and hippocampal volumes in 86 in-patients with unipolar depression and 87 healthy controls, and we then correlated amygdala and hippocampal volumes of 76 in-patients with the area under the curve of cortisol secretion in the dexamethasone/corticotropin releasing hormone (Dex/CRH) test at baseline and during short-term antidepressant therapy. In line with recently published studies both left and right amygdala volumes of patients in a first depressive episode were smaller than those of healthy controls. Patients with recurrent depressive episodes showed a reduction of hippocampal volumes, while amygdala volumes were normal. Larger left and right amygdala volumes correlated with a more pronounced reduction of HPA activity, measured by the cortisol secretion in the combined DEX/CRH test, during antidepressant therapy in patients with recurrent depressive episodes.
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- 2012
20. A variant of the neuronal amino acid transporter SLC6A15 is associated with ACTH and cortisol responses and cognitive performance in unipolar depression
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Anna Schuhmacher, U. Pfeiffer, Leonhard Lennertz, Vera Guttenthaler, Astrid Zobel, Rainald Mössner, Michael Wagner, Wolfgang Maier, and Susanne Höfels
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Cortisol secretion ,Adult ,Male ,endocrine system ,medicine.medical_specialty ,Cortisol awakening response ,Adolescent ,Hydrocortisone ,Nerve Tissue Proteins ,Adrenocorticotropic hormone ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Glucocorticoid receptor ,Cognition ,Adrenocorticotropic Hormone ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Pharmacology ,Depressive Disorder ,Genetic Variation ,Middle Aged ,medicine.disease ,3. Good health ,030227 psychiatry ,Psychiatry and Mental health ,Endocrinology ,medicine.anatomical_structure ,Glucocorticoid secretion ,Amino Acid Transport Systems, Neutral ,Major depressive disorder ,Female ,Psychology ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery ,Hypothalamic–pituitary–adrenal axis ,Biomarkers ,medicine.drug - Abstract
Major depressive disorder (MDD) is accompanied by both cognitive impairments and a hyperactivity of the hypothalamic–pituitary–adrenocortical (HPA) system, resulting in an enhanced glucocorticoid secretion. Cortisol acts via mineralocorticoid and glucocorticoid receptors densely located in the hippocampus, a brain area that is important regarding cognitive functions and especially memory functions. Recently, a variant (rs1545843) affecting transcription of the human SLC6A15 gene has been associated with depression in a genome-wide association study. In an animal model, the neuronal amino acid transporter SLC6A15 was found to be decreased in stress-susceptible mice. Against the background of stress impacting on the activity of the HPA axis, we have investigated alterations of adrenocorticotropic hormone (ACTH) and cortisol secretion in the combined dexamethasone/corticotrophin-releasing hormone (Dex/CRH) test as well as memory and attention performance in a sample of 248 patients with unipolar depression and 172 healthy control subjects genotyped for rs1545843. MDD patients carrying the depression-associated AA genotype showed enhanced maximum and area under the curve ACTH and cortisol answers (p = 0.03) as well as an impaired memory and impaired sustained attention performance (p = 0.04) compared to carriers of at least one G allele. No effects of the SLC6A15 variant were found in the healthy control group. Our findings argue for a role of the SLC6A15 gene in ACTH and cortisol secretion during the Dex/CRH test and furthermore in the occurrence of cognitive impairments in unipolar depression.
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- 2012
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21. Schizophrenia risk polymorphisms in the TCF4 gene interact with smoking in the modulation of auditory sensory gating
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Marion Clepce, Norbert Dahmen, Wolfgang Maier, Leonhard Lennertz, Noah Savary, Holger Thiele, Arian Mobascher, Nadine Petrovsky, Michael Nothnagel, Thomas F. Wienker, Gerhard Gründer, Ingo Frommann, Tomislav Majić, Norbert Thuerauf, Jürgen Gallinat, Michael Wagner, Falk Kiefer, Boris B. Quednow, Amalia Diaz-Lacava, Rainald Mössner, Jürgen Brinkmeyer, Katja N. Spreckelmeyer, Francesco Musso, Georg Winterer, Peter Nürnberg, and Mohammad R. Toliat
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Male ,Linkage disequilibrium ,Audiology ,Linkage Disequilibrium ,chemistry.chemical_compound ,Transcription Factor 4 ,0302 clinical medicine ,Gene Frequency ,physiopathology [Smoking] ,Risk Factors ,Germany ,genetics [Schizophrenia] ,physiology [Evoked Potentials, Auditory] ,Cotinine ,Prepulse inhibition ,Genetics ,education.field_of_study ,Multidisciplinary ,Geography ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,Smoking ,blood [Cotinine] ,blood [Smoking] ,Electroencephalography ,Biological Sciences ,genetics [Transcription Factors] ,Sensory Gating ,3. Good health ,medicine.anatomical_structure ,Schizophrenia ,physiology [Sensory Gating] ,Evoked Potentials, Auditory ,Female ,ddc:500 ,Adult ,medicine.medical_specialty ,Genotype ,Population ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Commentaries ,medicine ,Humans ,genetics [Basic Helix-Loop-Helix Leucine Zipper Transcription Factors] ,education ,Allele frequency ,Analysis of Variance ,Sensory gating ,medicine.disease ,030227 psychiatry ,chemistry ,Endophenotype ,physiopathology [Schizophrenia] ,TCF4 protein, human ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Several polymorphisms of the transcription factor 4 ( TCF4 ) have been shown to increase the risk for schizophrenia, particularly TCF4 rs9960767. This polymorphism is associated with impaired sensorimotor gating measured by prepulse inhibition—an established endophenotype of schizophrenia. We therefore investigated whether TCF4 polymorphisms also affect another proposed endophenotype of schizophrenia, namely sensory gating assessed by P50 suppression of the auditory evoked potential. Although sensorimotor gating and sensory gating are not identical, recent data suggest that they share genetic fundamentals. In a multicenter study at six academic institutions throughout Germany, we applied an auditory P50 suppression paradigm to 1,821 subjects (1,023 never-smokers, 798 smokers) randomly selected from the general population. Samples were genotyped for 21 TCF4 polymorphisms. Given that smoking is highly prevalent in schizophrenia and affects sensory gating, we also assessed smoking behavior, cotinine plasma concentrations, exhaled carbon monoxide, and the Fagerström Test (FTND). P50 suppression was significantly decreased in carriers of schizophrenia risk alleles of the TCF4 polymorphisms rs9960767, rs10401120rs, rs17597926, and 17512836 ( P < 0.0002–0.00005). These gene effects were modulated by smoking behavior as indicated by significant interactions of TCF4 genotype and smoking status; heavy smokers (FTND score ≥4) showed stronger gene effects on P50 suppression than light smokers and never-smokers. Our finding suggests that sensory gating is modulated by an interaction of TCF4 genotype with smoking, and both factors may play a role in early information processing deficits also in schizophrenia. Consequently, considering smoking behavior may facilitate the search for genetic risk factors for schizophrenia.
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- 2012
22. The functional coding variant Asn(107)Ile of the neuropeptide S receptor gene (NPSR1) is associated with schizophrenia and modulates verbal memory and the acoustic startle response
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Ingo Frommann, Michael Wagner, Anna Schuhmacher, Ralf Pukrop, Wolfgang Wölwer, Rainald Mössner, Leonhard Lennertz, Anja Steinbrecher, Wolfgang Gaebel, Wolfgang Maier, Joachim Klosterkötter, Martin W. Landsberg, Svenja Schulze-Rauschenbach, Petra Franke, Heinz Häfner, Nadine Petrovsky, Boris B. Quednow, Susanne Höfels, University of Zurich, and Mössner, R
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Male ,Reflex, Startle ,Startle response ,Neuropsychological Tests ,Receptors, G-Protein-Coupled ,2738 Psychiatry and Mental Health ,0302 clinical medicine ,2736 Pharmacology (medical) ,Pharmacology (medical) ,10064 Neuroscience Center Zurich ,Prepulse inhibition ,0303 health sciences ,medicine.diagnostic_test ,Sensory Gating ,Diagnostic and Statistical Manual of Mental Disorders ,Psychiatry and Mental health ,3004 Pharmacology ,Schizophrenia ,10076 Center for Integrative Human Physiology ,NMDA receptor ,Female ,Schizophrenic Psychology ,Memory consolidation ,Asparagine ,Psychology ,Algorithms ,Adult ,Genotype ,610 Medicine & health ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Memory ,Neuropeptide S ,mental disorders ,medicine ,Humans ,Isoleucine ,Neuropeptide S receptor ,030304 developmental biology ,Pharmacology ,Analysis of Variance ,Blinking ,DNA ,medicine.disease ,Acoustic Stimulation ,Amino Acid Substitution ,10054 Clinic for Psychiatry, Psychotherapy, and Psychosomatics ,570 Life sciences ,biology ,Verbal memory ,Neuroscience ,030217 neurology & neurosurgery - Abstract
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.
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- 2012
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23. Harm Avoidance And Childhood Adversities In Patients With Obsessive-Compulsive Disorder And Unaffected First-Degree Relatives: Evidence For A Diathesis-Stress Model
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Christian Kaufmann, Rosa Grützmann, Katharina Bey, Norbert Kathmann, Michael Wagner, Leonhard Lennertz, Julia Klawohn, Anja Riesel, and Stephan Heinzel
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Pharmacology ,medicine.medical_specialty ,media_common.quotation_subject ,medicine.disease ,behavioral disciplines and activities ,Diathesis–stress model ,Psychiatry and Mental health ,Neurology ,Endophenotype ,mental disorders ,medicine ,Harm avoidance ,Anxiety ,Personality ,Pharmacology (medical) ,Temperament and Character Inventory ,Neurology (clinical) ,medicine.symptom ,First-degree relatives ,Psychological abuse ,Psychology ,Psychiatry ,Biological Psychiatry ,Clinical psychology ,media_common - Abstract
Background Obsessive-compulsive disorder (OCD) is a severe psychiatric disorder, which aggregates in families. Its etiology is assumed to involve interactions between genetically determined vulnerability factors and critical environmental influences. In the present study, we aim to investigate how the personality trait harm avoidance and the experience of different childhood adversities contribute to the development of OCD. Methods One hundred and sixty-nine patients with OCD, 157 healthy comparison subjects and 57 unaffected first-degree relatives of OCD patients were examined by trained clinical psychologists using the Structured Clinical Interview for DSM-IV (SKID). Harm avoidance was assessed using the Temperament and Character Inventory (TCI) and the severity of childhood adversities was measured with the Childhood Adversity Questionnaire (CTQ). Associations with depressive and obsessive-compulsive symptoms were investigated using the Beck Depression Inventory-II (BDI-II) and the Obsessive-Compulsive Inventory-Revised (OCI-R). Results Both OCD patients and unaffected relatives showed elevated levels of harm avoidance compared to healthy volunteers. Furthermore, patients exhibited significantly higher scores than relatives. This linear pattern was observed throughout all subscales of harm avoidance, and remained stable after controlling for the severity of depressive and obsessive-compulsive symptoms. With regards to childhood adversities, OCD patients reported higher levels than unaffected relatives and healthy volunteers, specifically on the subscales emotional abuse, emotional neglect, and experience of inconsistencies. Discussion The present findings support the role of harm avoidance as a potential endophenotype of OCD, and provide further evidence for a diathesis-stress model. While patients with OCD and unaffected first-degree relatives share elevated levels of harm avoidance, a heightened severity of childhood adversity was only observed in patients. A predisposition to exaggerated anxiety responses may thus take different trajectories depending on adverse environmental influences during childhood. In future research, we aim to investigate the genetic and epigenetic mechanisms underlying these findings.
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- 2017
24. Impact of TCF4 on the genetics of schizophrenia
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Leonhard Lennertz, Wolfgang Maier, Michael Wagner, Jens Benninghoff, Boris B. Quednow, Rainald Mössner, University of Zurich, and Mössner, R
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medicine.medical_specialty ,Medizin ,610 Medicine & health ,Gating ,Neuropsychological Tests ,behavioral disciplines and activities ,2738 Psychiatry and Mental Health ,03 medical and health sciences ,Cognition ,Transcription Factor 4 ,0302 clinical medicine ,Memory ,mental disorders ,medicine ,2736 Pharmacology (medical) ,Humans ,Genetic Predisposition to Disease ,Pharmacology (medical) ,10064 Neuroscience Center Zurich ,Association (psychology) ,Psychiatry ,Biological Psychiatry ,Prepulse inhibition ,Polymorphism, Genetic ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,General Medicine ,Sensory Gating ,Verbal Learning ,Executive functions ,medicine.disease ,030227 psychiatry ,Psychiatry and Mental health ,Pharmacogenetics ,Schizophrenia ,10054 Clinic for Psychiatry, Psychotherapy, and Psychosomatics ,10076 Center for Integrative Human Physiology ,Endophenotype ,570 Life sciences ,biology ,Schizophrenic Psychology ,Verbal memory ,2803 Biological Psychiatry ,Neuroscience ,030217 neurology & neurosurgery ,Antipsychotic Agents ,Transcription Factors - Abstract
Mutations of the transcription factor 4 (TCF4) gene cause mental retardation with or without associated facial dysmorphisms and intermittent hyperventilation. Subsequently, a polymorphism of TCF4 was shown in a genome-wide association study to slightly increase the risk of schizophrenia. We have further analysed the impact of this TCF4 variant rs9960767 on early information processing and cognitive functions in schizophrenia patients. We have shown in a sample of 401 schizophrenia patients that TCF4 influences verbal memory in the Rey Auditory Verbal Learning Test. Contrary to expectations, carriers of the schizophrenia-associated allele showed better recognition, thus indicating that while TCF4 influences verbal memory, the TCF4-mediated schizophrenia risk is not determined by the influence of TCF4 on verbal memory. TCF4 does not impact on various other cognitive functions belonging to the domains of attention and executive functions. Moreover, in a pharmacogenetic approach, TCF4 does not modulate the improvement of positive or negative schizophrenia symptoms during treatment with antipsychotics. Finally, we have assessed a key electrophysiological endophenotype of schizophrenia, sensorimotor gating. As measured by prepulse inhibition, the schizophrenia risk allele C of TCF4 rs9960767 reduces sensorimotor gating. This indicates that TCF4 influences key mechanisms of information processing, which may contribute to the pathogenesis of schizophrenia.
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- 2011
25. Novel Schizophrenia Risk Gene TCF4 Influences Verbal Learning and Memory Functioning in Schizophrenia Patients
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Hans-Jürgen Möller, Leonhard Lennertz, Anna Schuhmacher, Michael Wagner, Dan Rujescu, Svenja Schulze-Rauschenbach, Wolfgang Maier, Petra Franke, Wolfgang Wölwer, Wolfgang Gaebel, Rainald Mössner, Heinz Häfner, Ingo Frommann, and Martin W. Landsberg
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Adult ,Male ,medicine.medical_specialty ,Genotype ,Audiology ,Verbal learning ,Polymorphism, Single Nucleotide ,behavioral disciplines and activities ,03 medical and health sciences ,Transcription Factor 4 ,0302 clinical medicine ,Memory ,Polymorphism (computer science) ,Schizophrenic Psychology ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,Psychiatry ,Association (psychology) ,Alleles ,Biological Psychiatry ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,TCF4 ,Verbal Learning ,medicine.disease ,030227 psychiatry ,Psychiatry and Mental health ,Neuropsychology and Physiological Psychology ,Schizophrenia ,Female ,Psychology ,Psychomotor Performance ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
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.
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- 2011
26. Evidence for specific cognitive deficits in visual information processing in patients with OCD compared to patients with unipolar depression
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Leonhard Lennertz, Michael Wagner, Svenja Schulze-Rauschenbach, Norbert Kathmann, Peter Falkai, Friederike Rampacher, and Andrea Vogeley
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Adult ,Male ,Obsessive-Compulsive Disorder ,medicine.medical_specialty ,Adolescent ,genetic structures ,Neuropsychological Tests ,behavioral disciplines and activities ,Spatial memory ,03 medical and health sciences ,0302 clinical medicine ,Visual memory ,Memory ,mental disorders ,medicine ,Humans ,Verbal fluency test ,Psychiatry ,Problem Solving ,Biological Psychiatry ,Cognitive deficit ,Pharmacology ,Analysis of Variance ,Depressive Disorder, Major ,Cognitive disorder ,Cognition ,Middle Aged ,medicine.disease ,030227 psychiatry ,Visual Perception ,Major depressive disorder ,Female ,medicine.symptom ,Verbal memory ,Cognition Disorders ,Psychology ,030217 neurology & neurosurgery ,Clinical psychology - Abstract
Objective Neuropsychological studies comparing cognitive performance in patients suffering from Obsessive-Compulsive Disorder (OCD) or Major Depressive Disorder (MDD) revealed deficits in the domains of verbal fluency and viso-motor speed/set shifting in both groups. Spatial working memory deficits, however, have been identified as specific markers of OCD. As yet, it has not been substantiated whether deficits in visual organization and complex visual memory are also specific to OCD and are not shared by MDD. Method Test performance in seven cognitive domains was assessed in 40 OCD patients, 20 MDD patients, and 40 healthy controls. Patient groups were matched according to severity of depressive symptoms. Results Deficits shared by both patient groups, as compared to controls, were found in delayed spatial recall and verbal fluency while verbal memory was normal in both patient groups. Only patients with OCD, but not MDD patients were impaired in the domains visual memory, viso-motor speed/set shifting, visual organization, and problem solving. In addition, OCD patients differed significantly from MDD subjects in visual organization and problem solving. Visual organization scores correlated significantly with severity of current compulsions in the OCD group ( r = −.324). Conclusions OCD patients demonstrate difficulties in visual organization and mental manipulation of complex visual material, which are not accounted for by depressive symptoms and which constitute a specific cognitive deficit of the disorder.
- Published
- 2010
27. Perceived parental rearing in subjects with obsessive-compulsive disorder and their siblings
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Friederike Rampacher, Leonhard Lennertz, Michael Wagner, Wolfgang Maier, Ralf Pukrop, Andrea Vogeley, Peter Falkai, Hans-Jörgen Grabe, Harald-J. Freyberger, Stephan Ruhrmann, Svenja Schulze-Rauschenbach, Klaus Meyer, Susanne Kraft, Susan Ettelt, Ulrich John, Corinna Reck, and Joachim Klosterkötter
- Subjects
Adult ,Male ,Obsessive-Compulsive Disorder ,Mothers ,Dysfunctional family ,Late onset ,behavioral disciplines and activities ,Developmental psychology ,Fathers ,Young Adult ,Child Rearing ,Obsessive compulsive ,mental disorders ,Humans ,In patient ,Age of Onset ,Child ,Father-Child Relations ,Depression (differential diagnoses) ,Parenting ,Child rearing ,Depression ,Siblings ,Middle Aged ,Mother-Child Relations ,humanities ,Parental warmth ,Psychiatry and Mental health ,Female ,Perception ,Age of onset ,Psychology ,Clinical psychology - Abstract
Lennertz L, Grabe HJ, Ruhrmann S, Rampacher F, Vogeley A, Schulze-Rauschenbach S, Ettelt S, Meyer K, Kraft S, Reck C, Pukrop R, John U, Freyberger HJ, Klosterkotter J, Maier W, Falkai P, Wagner M. Perceived parental rearing in subjects with obsessive–compulsive disorder and their siblings. Objective: Perceived parenting in patients suffering from obsessive–compulsive disorder (OCD) is examined. We attempted to overcome some methodological limitations of prior studies by taking age of onset, parental OCD and comorbid depression into consideration. In addition, we included data from unaffected siblings to corroborate information on parental rearing. Method: One hundred and twenty-two cases with OCD and 41 of their siblings as well as 59 healthy controls and 45 of their siblings completed the German short-version of the EMBU (FEE). Results: Obsessive–compulsive disorder cases reported less parental warmth and more parental rejection and control. Further analyses indicated that parenting is also associated with OCD in cases with late onset and cases without parents affected by OCD. OCD cases with comorbid depression described their parents particularly negatively. Data from siblings indicated good validity of perceived parenting in OCD. Conclusion: This study provides further evidence for dysfunctional child rearing being relevant to the development of OCD and depression.
- Published
- 2010
28. Replication of the association between CHRNA4 rs1044396 and harm avoidance in a large population-based sample
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Sebastian Markett, Falk Kiefer, Leonhard Lennertz, Norbert Dahmen, Katharina Bey, Georg Winterer, Katja N. Spreckelmeyer, Michael Wagner, Gerhard Gründer, Thomas F. Wienker, Johannes Kornhuber, Norbert Thuerauf, Arian Mobascher, Mohammad R. Toliat, Jürgen Gallinat, Peter Nürnberg, and Nadine Petrovsky
- Subjects
genetics [Receptors, Nicotinic] ,0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,media_common.quotation_subject ,Context (language use) ,Receptors, Nicotinic ,Polymorphism, Single Nucleotide ,Nicotine ,03 medical and health sciences ,0302 clinical medicine ,Harm Reduction ,Germany ,medicine ,Personality ,Humans ,Pharmacology (medical) ,ddc:610 ,Psychiatry ,Biological Psychiatry ,Genetic Association Studies ,media_common ,Pharmacology ,business.industry ,Smoking ,genetics [Smoking] ,medicine.disease ,Psychiatry and Mental health ,Nicotinic acetylcholine receptor ,030104 developmental biology ,Nicotinic agonist ,Neurology ,genetics [Personality] ,Anxiety ,Harm avoidance ,Cholinergic ,Female ,Neurology (clinical) ,medicine.symptom ,business ,nicotinic acetylcholine receptor alpha4 subunit ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Harm avoidance is a personality trait characterized by excessive worrying and fear of uncertainty, which has repeatedly been related to anxiety disorders. Converging lines of research in rodents and humans point towards an involvement of the nicotinic cholinergic system in the modulation of anxiety. Most notably, the rs1044396 polymorphism in the CHRNA4 gene, which codes for the α4 subunit of the nicotinic acetylcholine receptor, has been linked to negative emotionality traits including harm avoidance in a recent study. Against this background, we investigated the association between harm avoidance and the rs1044396 polymorphism using data from N=1673 healthy subjects, which were collected in the context of the German multi-centre study ׳Genetics of Nicotine Dependence and Neurobiological Phenotypes׳. Homozygous carriers of the C-allele showed significantly higher levels of harm avoidance than homozygous T-allele carriers, with heterozygous subjects exhibiting intermediate scores. The effect was neither modulated by age or gender nor by smoking status. By replicating previous findings in a large population-based sample for the first time, the present study adds to the growing evidence suggesting an involvement of nicotinic cholinergic mechanism in anxiety and negative emotionality, which may pose an effective target for medical treatment.
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- 2015
29. Neurocognitive functioning in parents of schizophrenia patients: Attentional and executive performance vary with genetic loading
- Author
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Leonhard Lennertz, Ulrich Ettinger, Jan Dreher, Joachim Klosterkötter, Stephan Ruhrmann, Wolfgang Maier, Nadine Petrovsky, Michael Wagner, Svenja Schulze-Rauschenbach, and Ralf Pukrop
- Subjects
Parents ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Endophenotypes ,Neuropsychological Tests ,behavioral disciplines and activities ,Executive Function ,Young Adult ,Cognition ,Risk Factors ,mental disorders ,medicine ,Humans ,Attention ,genetics [Schizophrenia] ,ddc:610 ,Family history ,Young adult ,Psychiatry ,Biological Psychiatry ,Aged ,Aged, 80 and over ,medicine.diagnostic_test ,Neuropsychology ,physiology [Cognition] ,Neuropsychological test ,Middle Aged ,medicine.disease ,physiology [Executive Function] ,Psychiatry and Mental health ,Schizophrenia ,Endophenotype ,physiology [Attention] ,Female ,psychology [Parents] ,Psychology ,Neurocognitive ,Clinical psychology - Abstract
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.
- Published
- 2015
30. Cross-Disorder Genome-Wide Analyses Suggest a Complex Genetic Relationship Between Tourette's Syndrome and OCD
- Author
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Mary M. Robertson, Peter Heutink, Leonhard Lennertz, Victor I. Reus, John Hardy, Mark A. Riddle, Beatriz Camarena, Helena Garrido, Robert A. King, Simon Girard, Christine Lochner, Michael H. Bloch, Patrick Evans, Anuar Konkashbaev, Jack Samuels, Priya Moorjani, Chiara Sabatti, Andrew J. Pakstis, Ying Wang, O. Joseph Bienvenu, Richard Delorme, David L. Pauls, Rainald Moessner, Gary A. Heiman, Daniel A. Geller, Marco A. Grados, Eric R. Gamazon, John Piacentini, Dan J. Stein, William Cornejo Ochoa, Maria Conceição do Rosário, Karin Egberts, Thomas L. Lowe, Christopher K. Edlund, Jan Smit, Christopher Pittenger, Denise A. Chavira, Marion Leboyer, Homero Vallada, Sandra Catalina Mesa Restrepo, Jacquelyn Crane, Donald W. Black, David V. Conti, Paul Sandor, Humberto Nicolini, Lisa Osiecki, Jeremy Veenstra-VanderWeele, Catherine Mayerfeld, Danielle Posthuma, Edna Grünblatt, Carolina Cappi, Robert B. Weiss, Cristina Barlassina, Sara Lupoli, Chunyu Liu, Sian M. J. Hemmings, Ben A. Oostra, D. Denys, Susanne Walitza, Lea K. Davis, Stephen A. Haddad, Luis Diego Herrera, Jubel Morgan, Hans Joergen Grabe, Benjamin M. Neale, Thomas V. Fernandez, Yehuda Pollak, Roel A. Ophoff, Gerald Nestadt, Harvey S. Singer, Stephan Ruhrmann, Bernadette Cullen, Michael Wagner, Nuria Lanzagorta, Jeremiah M. Scharf, Cathy L. Budman, Ruth D. Bruun, R. Kurlan, Valsama Eapen, Jesen Fagerness, Desmond Campbell, James L. Kennedy, Carlos N. Pato, Nancy J. Cox, Pieter J. Hoekstra, Joseph Jankovic, Cathy L. Barr, Peter Falkai, Donald L. Gilbert, Fortu Benarroch, Dianne M. Hezel, Maria Cristina Cavallini, Brooke Sheppard, Fabio Macciardi, William M. McMahon, Laura Bellodi, Maurizio Turiel, Wolfgang Maier, Varda Gross-Tsur, Helena Brentani, Dongmei Yu, Danielle C. Cath, Ana V. Valencia Duarte, Eduardo Fournier, James A. Knowles, Tobias J. Renner, Erika L. Nurmi, Guy A. Rouleau, Benjamin D. Greenberg, Nelson B. Freimer, Shaun Purcell, Patience J. Gallagher, Roxana Romero, Gregory L. Hanna, Paolo Manunta, Edwin H. Cook, Michele T. Pato, Sylvain Chouinard, Scott L. Rauch, James T. McCracken, Gloria Gerber, Carol A. Mathews, Jens R. Wendland, Sampath Arepalli, Dennis L. Murphy, Daniele Cusi, Barbara Kremeyer, Vladimir Coric, Aline S. Sampaio, Erika Salvi, Julio C. Cardona Silgado, Cornelia Illmann, James F. Leckman, Euripedes Constantino Miguel, H. Müller, Yin Yao Shugart, Eric Strengman, Ana Gabriela Hounie, Michael E. Weale, Gabriel Bedoya Berrió, Margaret A. Richter, Maurizio Marconi, Allan L. Naarden, Michael A. Jenike, M.R. Cookson, David R. Rosenberg, Andres Ruiz-Linares, S. Evelyn Stewart, Paul D. Arnold, H.G.M. Westenberg, Yves Dion, Jay A. Tischfield, Eske M. Derks, Lauren M. McGrath, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Yu, D., Mathews, C. A., Scharf, J. M., Neale, B. M., Davis, L. K., Gamazon, E. R., Derks, E. M., Evans, P., Edlund, C. K., Crane, J., Fagerness, J. A., Osiecki, L., Gallagher, P., Gerber, G., Haddad, S., Illmann, C., Mcgrath, L. M., Mayerfeld, C., Arepalli, S., Barlassina, C., Barr, C. L., Bellodi, L., Benarroch, F., Berrio, G. B., Bienvenu, O. J., Black, D., Bloch, M. H., Brentani, H., Bruun, R. D., Budman, C. L., Camarena, B., Campbell, D. D., Cappi, C., Cardona Silgado, J. C., Cavallini, M. C., Chavira, D. A., Chouinard, S., Cook, E. H., Cookson, M. R., Coric, V., Cullen, B., Cusi, D., Delorme, R., Denys, D., Dion, Y., Eapen, V., Egberts, K., Falkai, P., Fernandez, T., Fournier, E., Garrido, H., Geller, D., Gilbert, D., Girard, S. L., Grabe, H. J., Grados, M. A., Greenberg, B. D., Gross-Tsur, V., Grunblatt, E., Hardy, J., Heiman, G. A., Hemmings, S. M. J., Herrera, L. D., Hezel, D. M., Hoekstra, P. J., Jankovic, J., Kennedy, J. L., King, R. A., Konkashbaev, A. I., Kremeyer, B., Kurlan, R., Lanzagorta, N., Leboyer, M., Leckman, J. F., Lennertz, L., Liu, C., Lochner, C., Lowe, T. L., Lupoli, S., Macciardi, F., Maier, W., Manunta, P., Marconi, M., Mccracken, J. T., Mesa Restrepo, S. C., Moessner, R., Moorjani, P., Morgan, J., Muller, H., Murphy, D. L., Naarden, A. L., Ochoa, W. C., Ophoff, R. A., Pakstis, A. J., Pato, M. T., Pato, C. N., Piacentini, J., Pittenger, C., Pollak, Y., Rauch, S. L., Renner, T., Reus, V. I., Richter, M. A., Riddle, M. A., Robertson, M. M., Romero, R., Rosario, M. C., Rosenberg, D., Ruhrmann, S., Sabatti, C., Salvi, E., Sampaio, A. S., Samuels, J., Sandor, P., Service, S. K., Sheppard, B., Singer, H. S., Smit, J. H., Stein, D. J., Strengman, E., Tischfield, J. A., Turiel, M., Valencia Duarte, A. V., Vallada, H., Veenstra-VanderWeele, J., Walitza, S., Walkup, J., Wang, Y., Weale, M., Weiss, R., Wendland, J. R., Westenberg, H. G. M., Yao, Y., Hounie, A. G., Miguel, E. C., Nicolini, H., Wagner, M., Ruiz-Linares, A., Cath, D. C., Mcmahon, W., Posthuma, D., Oostra, B. A., Nestadt, G., Rouleau, G. A., Purcell, S., Jenike, M. A., Heutink, P., Hanna, G. L., Conti, D. V., Arnold, P. D., Freimer, N., Stewart, S. E., Knowles, J. A., Cox, N. J., Pauls, D. L., Netherlands Institute for Neuroscience (NIN), Sub String Theory Cosmology and ElemPart, Leerstoel Hout, Experimental psychopathology, Psychiatry, Human genetics, NCA - Neurobiology of mental health, EMGO - Mental health, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Other departments, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Adult Psychiatry, Complex Trait Genetics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, and EMGO+ - Mental Health
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Adult ,Male ,Obsessive-Compulsive Disorder ,diagnosis [Tourette Syndrome] ,Tics ,Single-nucleotide polymorphism ,Genome-wide association study ,Comorbidity ,VARIANTS ,Tourette syndrome ,Polymorphism, Single Nucleotide ,Severity of Illness Index ,ASSOCIATION SCANS ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Polymorphism (computer science) ,Severity of illness ,mental disorders ,medicine ,TICS ,Humans ,ddc:610 ,Polymorphism ,030304 developmental biology ,Genetics ,Psychiatric Status Rating Scales ,genetics [Obsessive-Compulsive Disorder] ,0303 health sciences ,GENERALIST GENES ,Single Nucleotide ,OBSESSIVE-COMPULSIVE DISORDER ,epidemiology [Tourette Syndrome] ,medicine.disease ,Genetic architecture ,Psychiatry and Mental health ,genetics [Tourette Syndrome] ,Female ,epidemiology [Obsessive-Compulsive Disorder] ,Psychology ,030217 neurology & neurosurgery ,diagnosis [Obsessive-Compulsive Disorder] ,Genome-Wide Association Study ,Tourette Syndrome - Abstract
Objective: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD.Method: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders Polygenic score analyses identified a significant polygenic component for OCD (p=2x10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).Conclusions: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring burette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.
- Published
- 2015
31. 5-HT3 receptor influences the washing phenotype and visual organization in obsessive-compulsive disorder supporting 5-HT3 receptor antagonists as novel treatment option
- Author
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Peter Falkai, Vera Guttenthaler, Svenja Schulze-Rauschenbach, Leonhard Lennertz, Friederike Rampacher, Ralf Pukrop, Wolfgang Maier, Petra Franke, Rainald Mössner, Stephan Ruhrmann, Jens Benninghoff, Hans J. Grabe, Joachim Klosterkötter, Michael Wagner, and Andrea Vogeley
- Subjects
Male ,Oncology ,Obsessive-Compulsive Disorder ,Candidate gene ,Medizin ,Neuropsychological Tests ,HTR3E ,HTR3D ,0302 clinical medicine ,Germany ,HTR3C ,HTR3B ,Pharmacology (medical) ,biology ,Middle Aged ,humanities ,3. Good health ,Psychiatry and Mental health ,Phenotype ,Neurology ,Compulsive Behavior ,Visual Perception ,Female ,Psychology ,Adult ,medicine.medical_specialty ,Adolescent ,Genotype ,Polymorphism, Single Nucleotide ,behavioral disciplines and activities ,5-HT3 receptor ,Young Adult ,03 medical and health sciences ,Internal medicine ,mental disorders ,medicine ,Humans ,Psychiatry ,Genetic Association Studies ,Biological Psychiatry ,Aged ,Family Health ,Psychiatric Status Rating Scales ,Pharmacology ,030227 psychiatry ,Case-Control Studies ,Endophenotype ,Adjunctive treatment ,biology.protein ,Neurology (clinical) ,Receptors, Serotonin, 5-HT3 ,Cognition Disorders ,030217 neurology & neurosurgery - Abstract
A role of the HTR 3 A-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 HTR 3 A-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 HTR 3 E 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 HTR 3 E c.256G/c.256G-genotype performed significantly worse ( p =0.007). The case-control analyses revealed a nominal significant association of the HTR 3 D variant rs1000592 (p.H52R) with OCD ( p =0.029) which was also evident after combination of the case-control and the trio-results ( p =0.024). In male subjects, the variant rs6766410 (p.N163K) located in the HTR 3 C was significantly associated with OCD ( p =0.007). The association findings of the HTR 3 C and the HTR 3 E remained significant after correction for the number of variants investigated. These findings indicate a role of common variants of the HTR 3 A-E genes in OCD and OCD-related phenotypes and further support the use of 5-HT3 receptor antagonists as novel treatment options. The HTR 3 E gene is a novel candidate gene impacting on the individual expression of OC symptoms and OCD-related cognitive dysfunction.
- Published
- 2014
32. Nicotine enhances antisaccade performance in schizophrenia patients and healthy controls
- Author
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Leonhard Lennertz, Martin W. Landsberg, Judith Drees, Birgitta Sträter, Ingo Frommann, Nadine Petrovsky, Wolfgang Maier, Michael Wagner, Norbert Dahmen, Rainald Mössner, Katharina Heilmann, Henrik Kessler, Boris B. Quednow, Ulrich Ettinger, University of Zurich, and Petrovsky, Nadine
- Subjects
Male ,medicine.medical_treatment ,Statistics as Topic ,Nicotine ,2738 Psychiatry and Mental Health ,0302 clinical medicine ,2736 Pharmacology (medical) ,Pharmacology (medical) ,Nicotinic Agonists ,Cotinine ,Cross-Over Studies ,Smoking ,Cognition ,Middle Aged ,16. Peace & justice ,3. Good health ,Psychiatry and Mental health ,Nicotinic acetylcholine receptor ,3004 Pharmacology ,Schizophrenia ,Female ,Smoking status ,Psychology ,medicine.drug ,Clinical psychology ,Adult ,medicine.medical_specialty ,Adolescent ,Nicotine patch ,610 Medicine & health ,Administration, Cutaneous ,Young Adult ,03 medical and health sciences ,Double-Blind Method ,Internal medicine ,Reaction Time ,Saccades ,medicine ,Humans ,Effects of sleep deprivation on cognitive performance ,Beneficial effects ,Pharmacology ,Analysis of Variance ,medicine.disease ,030227 psychiatry ,Electrooculography ,10054 Clinic for Psychiatry, Psychotherapy, and Psychosomatics ,030217 neurology & neurosurgery - Abstract
Nicotine has been proposed to be a cognitive enhancer, particularly in schizophrenia patients. So far, the published studies of nicotine effects on antisaccade performance in schizophrenia patients only tested participants who were deprived smokers. Thus, we aimed to test both smoking and non-smoking patients as well as healthy controls in order to extend previous findings. Moreover, we employed a paradigm using standard and delayed trials. We hypothesized that, if nicotine is a genuine cognitive enhancer, its administration would improve antisaccade performance both in smoking and non-smoking participants. A total of 22 patients with schizophrenia (12 smokers and 10 non-smokers) and 26 controls (14 smokers and 12 non-smokers) completed the study. The effects of a nicotine patch (14 mg for smokers, 7 mg for non-smokers) on antisaccade performance were tested in a randomized, double-blind, placebo-controlled, cross-over trial. Schizophrenia patients made significantly more antisaccade errors than controls (p = 0.03). Both patients and controls made fewer antisaccade errors in the delayed trials than in the standard trials (p < 0.0001). Nicotine significantly reduced antisaccade error rate in the standard trials, but not in the delayed trials (p = 0.02). Smoking status did not influence the nicotine effect on antisaccade error rate (p = 0.10) indicating an equal procognitive effect of nicotine in smokers and non-smokers. Overall the present findings indicate that beneficial effects of nicotine on antisaccade performance are not confined to smoking schizophrenia patients. Instead, the findings likely represent genuine nicotine-induced enhancement of cognitive performance.
- Published
- 2013
33. Characterization of SLITRK1 Variation in Obsessive-Compulsive Disorder
- Author
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Vladimir Makarov, Leonhard Lennertz, Guiqing Cai, Stephan Ruhrmann, Joseph D. Buxbaum, Stephan Züchner, Hans J. Grabe, Peter Falkai, Wolfgang Maier, Rainald Moessner, Catalina Betancur, Dennis L. Murphy, Richard Delorme, Uzoezi Ozomaro, Dorothy E. Grice, Yuji Kajiwara, Michael Wagner, Seungtai Yoon, Betancur, Catalina, John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Department of Neuroscience, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Friedman Brain Institute, Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry and Psychotherapy, University of Cologne, University of Homburg, Universität Greifswald - University of Greifswald, Rheinische Friedrich-Wilhelms-Universität Bonn, Laboratory of Clinical Science, NIMH Intramural Research Program, National Institute of Mental Health, Division of Tics, Obsessive-Compulsive and Related Disorders, This work was supported by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award (UO, F31MH086275), the Lois Pope LIFE Fellowship (UO), the Beatrice and Samuel A. Seaver Foundation (JDB), and the New Jersey Center for Tourette Syndrome and Associated Disorders and the National Tourette Syndrome Association (DEG), the German Research Foundation DFG (PF, MW, WM, HJG, grant Fa 731/6) and Fondamental Foundation, Creteil, France (R.D)., and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,Obsessive-Compulsive Disorder ,Genetic Screens ,lcsh:Medicine ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,Tourette syndrome ,Mice ,0302 clinical medicine ,Missense mutation ,Spectrum disorder ,Child ,lcsh:Science ,Psychiatry ,Genetics ,0303 health sciences ,Multidisciplinary ,Neuronal Morphology ,Mental Disorders ,Brain ,Genomics ,Middle Aged ,SLITRK1 Gene ,Anxiety Disorders ,SLITRK1 ,humanities ,3. Good health ,Phenotype ,Mental Health ,Medicine ,Female ,Research Article ,Adult ,Molecular Sequence Data ,Mutation, Missense ,Nerve Tissue Proteins ,Biology ,behavioral disciplines and activities ,03 medical and health sciences ,Genome Analysis Tools ,Genetic Mutation ,Genetic variation ,mental disorders ,Neurites ,medicine ,Animals ,Humans ,Amino Acid Sequence ,030304 developmental biology ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Sequence Homology, Amino Acid ,lcsh:R ,Case-control study ,Genetic Variation ,Membrane Proteins ,Computational Biology ,medicine.disease ,Twin study ,Case-Control Studies ,Cellular Neuroscience ,Mutation ,lcsh:Q ,Gene Function ,030217 neurology & neurosurgery ,Tourette Syndrome ,Neuroscience - Abstract
International audience; Obsessive compulsive disorder (OCD) is a syndrome characterized by recurrent and intrusive thoughts and ritualistic behaviors or mental acts that a person feels compelled to perform. Twin studies, family studies, and segregation analyses provide compelling evidence that OCD has a strong genetic component. The SLITRK1 gene encodes a developmentally regulated stimulator of neurite outgrowth and previous studies have implicated rare variants in this gene in disorders in the OC spectrum, specifically Tourette syndrome (TS) and trichotillomania (TTM). The objective of the current study was to evaluate rare genetic variation in SLITRK1 in risk for OCD and to functionally characterize associated coding variants. We sequenced SLITRK1 coding exons in 381 individuals with OCD as well as in 356 control samples and identified three novel variants in seven individuals. We found that the combined mutation load in OCD relative to controls was significant (p = 0.036). We identified a missense N400I change in an individual with OCD, which was not found in more than 1000 control samples (P
- Published
- 2013
34. Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture
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Patrick Evans, Jay A. Tischfield, Anuar Konkashbaev, Richard Delorme, Sandra Catalina Mesa Restrepo, Margaret A. Richter, Gregory L. Hanna, Allan L. Naarden, Michele T. Pato, Jian Yang, Denise A. Chavira, Damiaan Denys, Paul Sandor, Michael A. Jenike, Sian M. J. Hemmings, Paul D. Arnold, Stephan Ruhrmann, H.G.M. Westenberg, Yves Dion, Cathy L. Barr, Andres Ruiz-Linares, Brooke Sheppard, Leonhard Lennertz, Eske M. Derks, Lauren M. McGrath, Barbara Kremeyer, Marion Leboyer, Victor I. Reus, Cornelia Illmann, S. Evelyn Stewart, Dan J. Stein, Ana Gabriela Hounie, James T. McCracken, R. Kurlan, Chunyu Liu, Aline S. Sampaio, Thomas L. Lowe, Benjamin M. Neale, Yehuda Pollak, Desmond Campbell, Fabio Macciardi, Mary M. Robertson, Benjamin D. Greenberg, Ben A. Oostra, Rainald Moessner, Gary A. Heiman, Nuria Lanzagorta, Sylvain Chouinard, Rianne M. Blom, Karin Egberts, Carlos N. Pato, David V. Conti, Carol A. Mathews, Ying Wang, Marco A. Grados, Julio C. Cardona Silgado, S. Hong Lee, H. Müller, Eric R. Gamazon, Humberto Nicolini, Jan Smit, Euripedes Constantino Miguel, Jens R. Wendland, Cathy L. Budman, Laura Bellodi, Danielle Posthuma, Jubel Morgan, David R. Rosenberg, John Piacentini, Hans J. Grabe, Mark A. Riddle, Beatriz Camarena, Naomi R. Wray, Eric Strengman, Dennis L. Murphy, Simon Girard, Christine Lochner, Ruth D. Bruun, Joseph Jankovic, Edwin H. Cook, William M. McMahon, Scott L. Rauch, James F. Leckman, Peter Falkai, Fortu Benarroch, Christopher K. Edlund, Gabriel Bedoya Berrío, Homero Vallada, Susanne Walitza, Nelson B. Freimer, Stephen A. Haddad, Yin Yao Shugart, Danielle C. Cath, Nancy J. Cox, Varda Gross-Tsur, Guy A. Rouleau, Bernadette Cullen, Michael H. Bloch, Dieter Deforce, David L. Pauls, Thomas V. Fernandez, Roel A. Ophoff, Filip Van Nieuwerburgh, Gerald Nestadt, Dongmei Yu, Helena Garrido, Robert A. King, James L. Kennedy, Clare L. Keenan, Lisa Osiecki, Jack Samuels, Jeremy Veenstra-VanderWeele, Ana V. Valencia Duarte, James A. Knowles, Patience J. Gallagher, Carolina Cappi, Maria Conceição do Rosário, Andrew J. Pakstis, Christopher Pittenger, Michael Wagner, Jeremiah M. Scharf, Daniel A. Geller, Vladimir Coric, Tobias J. Renner, Oscar J. Bienvenu, Roxana Romero, William Cornejo Ochoa, Peter Heutink, Lea K. Davis, Harvey S. Singer, Maria Cristina Cavallini, Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, Department of Psychiatry and Mental Health, Faculty of Health Sciences, Univ Chicago, Harvard Univ, Broad Inst Harvard & MIT, Univ Amsterdam, Massachusetts Gen Hosp, Univ Queensland, Univ Hlth Network, Hosp Sick Children, Univ Vita Salute San Raffaele, Hadassah Hebrew Univ Med Ctr, Univ Pontificia Bolivariana, Johns Hopkins Univ, Yale Univ, North Shore Long Isl Jewish Med Ctr, NYU Med Ctr, North Shore Long Isl Jewish Hlth Syst, Hofstra Univ, Inst Nacl Psiquiatria Ramon de la Fuente Muniz, UCL, Univ Hong Kong, Universidade de São Paulo (USP), Vrije Univ Amsterdam, Univ Utrecht, Altrecht Acad Anxiety Ctr, Univ Milan, Univ Calif Los Angeles, Univ Calif San Diego, Univ Montreal, Univ Illinois, Univ Ghent, Inst Pasteur, French Natl Sci Fdn, Hop Robert Debre, Univ Wurzburg, Univ Munich, Univ Med Greifswald, Butler Hosp, Shaare Zedek Med Ctr, Rutgers State Univ, Univ Stellenbosch, Baylor Coll Med, Ctr Addict & Mental Hlth, Univ Toronto, Overlook Hosp, Carracci Med Grp, Inst Mondor Rech Biomed, Univ Bonn, Univ Calif San Francisco, UCI, Univ Utah, NIMH Intramural Res Program, Med City Dallas Hosp, Univ Med Ctr, Univ So Calif, Partners Psychiat & McLean Hosp, Sunnybrook Hlth Sci Ctr, St George Hosp, Sch Med, Hosp Nacl Ninos Dr Carlos Saenz Herrera, Universidade Federal de São Paulo (UNIFESP), Wayne State Univ, Detroit Med Ctr, McGill Univ, Univ Cologne, Universidade Federal da Bahia (UFBA), Youthdale Treatment Ctr, Johns Hopkins Univ Sch Med, Univ Cape Town, Univ Med Ctr Utrecht, Vanderbilt Univ, Univ Zurich, Inst Royal Netherlands Acad Arts & Sci NIN KNAW, Natl Inst Genom Med SAP, Vrije Univ Amsterdam Med Ctr, Erasmus Univ, Univ Michigan, German Ctr Neurodegenerat Dis, Erasmus MC, Univ British Columbia, Brigham & Womens Hosp, Davis, Lk, Yu, D, Keenan, Cl, Gamazon, Er, Konkashbaev, Ai, Derks, Em, Neale, Bm, Yang, J, Lee, Sh, Evans, P, Barr, Cl, Bellodi, Laura, Benarroch, F, Berrio, Gb, Bienvenu, Oj, Bloch, Mh, Blom, Rm, Bruun, Rd, Budman, Cl, Camarena, B, Campbell, D, Cappi, C, Cardona Silgado, Jc, Cath, Dc, Cavallini, Mc, Chavira, Da, Chouinard, S, Conti, Dv, Cook, Eh, Coric, V, Cullen, Ba, Deforce, D, Delorme, R, Dion, Y, Edlund, Ck, Egberts, K, Falkai, P, Fernandez, Tv, Gallagher, Pj, Garrido, H, Geller, D, Girard, Sl, Grabe, Hj, Grados, Ma, Greenberg, Bd, Gross Tsur, V, Haddad, S, Heiman, Ga, Hemmings, Sm, Hounie, Ag, Illmann, C, Jankovic, J, Jenike, Ma, Kennedy, Jl, King, Ra, Kremeyer, B, Kurlan, R, Lanzagorta, N, Leboyer, M, Leckman, Jf, Lennertz, L, Liu, C, Lochner, C, Lowe, Tl, Macciardi, F, Mccracken, Jt, Mcgrath, Lm, Mesa Restrepo, Sc, Moessner, R, Morgan, J, Muller, H, Murphy, Dl, Naarden, Al, Ochoa, Wc, Ophoff, Ra, Osiecki, L, Pakstis, Aj, Pato, Mt, Pato, Cn, Piacentini, J, Pittenger, C, Pollak, Y, Rauch, Sl, Renner, Tj, Reus, Vi, Richter, Ma, Riddle, Ma, Robertson, Mm, Romero, R, Rosàrio, Mc, Rosenberg, D, Rouleau, Ga, Ruhrmann, S, Ruiz Linares, A, Sampaio, A, Samuels, J, Sandor, P, Sheppard, B, Singer, H, Smit, Jh, Stein, Dj, Strengman, E, Tischfield, Ja, Valencia Duarte, Av, Vallada, H, Van Nieuwerburgh, F, Veenstra Vanderweele, J, Walitza, S, Wang, Y, Wendland, Jr, Westenberg, Hg, Shugart, Yy, Miguel, Ec, Mcmahon, W, Wagner, M, Nicolini, H, Posthuma, D, Hanna, Gl, Heutink, P, Denys, D, Arnold, Pd, Oostra, Ba, Nestadt, G, Freimer, Nb, Pauls, Dl, Wray, Nr, Stewart, Se, Mathews, Ca, Knowles, Ja, Cox, Nj, Scharf, Jm, Functional Genomics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Davis, Lea K, Yu, Dongmei, Keenan, Clare L, Gamazon, Eric R, Lee, S Hong, Scharf, Jeremiah M, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Other departments, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Adult Psychiatry, and Graduate School
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Cancer Research ,Obsessive-Compulsive Disorder ,COMPLEX DISEASES ,Genome-wide association study ,heritability ,Genome-wide association studies ,neurobehavioral disorders ,COMMON SNPS ,0302 clinical medicine ,Gene Frequency ,Missing heritability problem ,MISSING HERITABILITY ,Cerebellum ,Heritability of autism ,BRAIN ,Genetics (clinical) ,Genetics ,ddc:616 ,Genetics & Heredity ,0303 health sciences ,Chromosome 15 ,humanities ,FAMILY ,obsessive-compulsive disorder ,genetics [Tourette Syndrome] ,Phenotype ,NEUROPSYCHIATRIC DISORDERS ,GENÔMICA ,Research Article ,EXPRESSION ,lcsh:QH426-470 ,SNP ,Biology ,Quantitative trait locus ,Genome-wide Complex Trait Analysis ,Genetic correlation ,behavioral disciplines and activities ,Polymorphism, Single Nucleotide ,Chromosomes ,TIC DISORDERS ,03 medical and health sciences ,Quantitative Trait, Heritable ,mental disorders ,genetic risk factors ,Humans ,ddc:610 ,AUTISM ,Variant genotypes ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,genetics [Obsessive-Compulsive Disorder] ,Tourette syndrome ,Parietal lobe ,Biology and Life Sciences ,Heritability ,Genetic architecture ,Minor allele frequency ,Trastorno Obsesivo Compulsivo ,lcsh:Genetics ,pathology [Obsessive-Compulsive Disorder] ,genetic variation ,pathology [Tourette Syndrome] ,Síndrome de Tourette ,030217 neurology & neurosurgery ,GILLES ,Genome-Wide Association Study ,Tourette Syndrome - Abstract
The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures., Author Summary Family and twin studies have shown that genetic risk factors are important in the development of Tourette Syndrome (TS) and obsessive compulsive disorder (OCD). However, efforts to identify the individual genetic risk factors involved in these two neuropsychiatric disorders have been largely unsuccessful. One possible explanation for this is that many genetic variations scattered throughout the genome each contribute a small amount to the overall risk. For TS and OCD, the genetic architecture (characterized by the number, frequency, and distribution of genetic risk factors) is presently unknown. This study examined the genetic architecture of TS and OCD in a variety of ways. We found that rare genetic changes account for more genetic risk in TS than in OCD; certain chromosomes contribute to OCD risk more than others; and variants that influence the level of genes expressed in two regions of the brain can account for a significant amount of risk for both TS and OCD. Results from this study might help in determining where, and what kind of variants are individual risk factors for TS and OCD and where they might be located in the human genome.
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- 2013
35. Investigation of tryptophan hydroxylase 2 (TPH2) in schizophrenia and in the response to antipsychotics
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Leonhard Lennertz, Michael Wagner, Heinz Häfner, Anna Schuhmacher, Dan Rujescu, Rainald Mössner, Boris B. Quednow, Wolfgang Maier, Petra Franke, Marcella Rietschel, Wolfgang Wölwer, Tim Becker, Jens Benninghoff, Wolfgang Gaebel, University of Zurich, and Schuhmacher, Anna
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Male ,medicine.medical_treatment ,drug therapy [Schizophrenia] ,Medizin ,Pharmacology ,genetics [Cognition Disorders] ,Neuropsychological Tests ,Tryptophan Hydroxylase ,Linkage Disequilibrium ,2738 Psychiatry and Mental Health ,0302 clinical medicine ,Gene Frequency ,genetics [Schizophrenia] ,International HapMap Project ,drug therapy [Gait Disorders, Neurologic] ,TPH1 ,Positive and Negative Syndrome Scale ,TPH2 ,Middle Aged ,3. Good health ,Psychiatry and Mental health ,Schizophrenia ,therapeutic use [Antipsychotic Agents] ,10076 Center for Integrative Human Physiology ,genetics [Polymorphism, Single Nucleotide] ,Female ,Schizophrenic Psychology ,Psychology ,2803 Biological Psychiatry ,genetics [Tryptophan Hydroxylase] ,Antipsychotic Agents ,Adult ,medicine.medical_specialty ,Genotype ,genetics [Gait Disorders, Neurologic] ,610 Medicine & health ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,etiology [Gait Disorders, Neurologic] ,Young Adult ,Internal medicine ,complications [Schizophrenia] ,medicine ,Humans ,ddc:610 ,Antipsychotic ,Gait Disorders, Neurologic ,Biological Psychiatry ,Genetic Association Studies ,Aged ,Psychiatric Status Rating Scales ,Analysis of Variance ,TPH2 protein, human ,Haplotype ,etiology [Cognition Disorders] ,drug therapy [Cognition Disorders] ,Tryptophan hydroxylase ,medicine.disease ,030227 psychiatry ,Endocrinology ,Pharmacogenetics ,10054 Clinic for Psychiatry, Psychotherapy, and Psychosomatics ,Case-Control Studies ,570 Life sciences ,biology ,Cognition Disorders ,030217 neurology & neurosurgery - Abstract
Serotonergic transmission is considered relevant in the pathophysiology and the treatment of schizophrenia. Tryptophan hydroxylase (TPH) is the rate limiting enzyme in the biosynthesis of serotonin. While the TPH1 gene has been found to be associated with schizophrenia, studies focusing on TPH2 variants did not yield conclusive results for schizophrenia or the response to antipsychotic medication. We analyzed eleven TPH2 SNPs in two case-control samples consisting of 4453 individuals in total. Six SNPs were selected because of their potential functional relevance (rs4570625, rs11178997, rs11178998, rs7954758, rs7305115, and, rs4290270) and were supported by another 5 tagging SNPs selected based on HapMap LD information. In the discovery sample (1476 individuals), we observed a significant association with schizophrenia for rs10784941 (p = 0.009, OR minor G-allele 0.82 [0.71-0.95]) and rs4565946 (p = 0.011, OR minor T-allele 0.83 [0.71-0.96]). Association was also observed with a common rs4570625-rs4565946 haplotype (OR G-C haplotype 1.20 [1.02-1.40]; p = 0.0046). Single-marker associations could not be replicated in the replication sample consisting of 2977 individuals, but there was a strong trend regarding the rs4570625-rs4565946 G-C haplotype (OR 1.10 [0.98-1.24]; p(one-sided test) = 0.054). In smaller sub-samples, the rare rs4570625-rs4565946 T-T haplotype was associated with reduced processing speed (n = 193, p = 0.004) and sensorimotor gating (n = 68, p = 0.006) of schizophrenia patients. TPH2 variants and the rs4570625-rs4565946 G-C haplotype did not influence the beneficial response to antipsychotic drugs (n = 210) after four weeks of treatment administering the Positive and Negative Syndrome Scale of Schizophrenia (PANSS). We also investigated the association of the SNPs to treatment response, but did not get significant results. In sum, our results argue for only a minor role of TPH2 in schizophrenia.
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- 2012
36. Antisaccade performance in patients with obsessive-compulsive disorder and unaffected relatives: further evidence for impaired response inhibition as a candidate endophenotype
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Joachim Klosterkötter, Michael Wagner, Leonhard Lennertz, Andrea Vogeley, Stephan Ruhrmann, Friederike Rampacher, Peter Falkai, Wolfgang Maier, Svenja Schulze-Rauschenbach, and Ralf Pukrop
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Adult ,Male ,medicine.medical_specialty ,Obsessive-Compulsive Disorder ,Endophenotypes ,Audiology ,Neuropsychological Tests ,behavioral disciplines and activities ,mental disorders ,medicine ,Reaction Time ,Saccades ,Humans ,Pharmacology (medical) ,Psychiatry ,Biological Psychiatry ,Family Health ,Psychiatric Status Rating Scales ,Analysis of Variance ,medicine.diagnostic_test ,Neuropsychology ,Cognition ,General Medicine ,Neuropsychological test ,Electrooculography ,Middle Aged ,Verbal reasoning ,humanities ,Psychiatry and Mental health ,Inhibition, Psychological ,Endophenotype ,Female ,Analysis of variance ,Antisaccade task ,Psychology ,Cognition Disorders ,Photic Stimulation - Abstract
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.
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- 2011
37. A promoter variant of SHANK1 affects auditory working memory in schizophrenia patients and in subjects clinically at risk for psychosis
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Ralf Pukrop, Svenja Schulze-Rauschenbach, Leonhard Lennertz, Anna Schuhmacher, Andreas Bechdolf, Michael Alexander, Michael Wagner, Rainald Mössner, Heinz Häfner, Petra Franke, Anja Steinbrecher, Wolfgang Maier, Wolfgang Wölwer, Stephan Ruhrmann, Julia Berning, Martin W. Landsberg, Ingo Frommann, Wolfgang Gaebel, and Joachim Klosterkötter
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Adult ,Male ,Psychosis ,Genotype ,Nerve Tissue Proteins ,Neuropsychological Tests ,Bioinformatics ,Prodrome ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Risk Factors ,medicine ,Memory span ,Humans ,Pharmacology (medical) ,Prefrontal cortex ,Promoter Regions, Genetic ,Biological Psychiatry ,Clozapine ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,Aged ,Psychiatric Status Rating Scales ,0303 health sciences ,Memory Disorders ,Working memory ,At risk mental state ,General Medicine ,Middle Aged ,medicine.disease ,3. Good health ,Psychiatry and Mental health ,Memory, Short-Term ,Acoustic Stimulation ,Psychotic Disorders ,Schizophrenia ,Female ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Mutations in postsynaptic scaffolding genes contribute to autism, thus suggesting a role in pathological processes in neurodevelopment. Recently, two de novo mutations in SHANK3 were described in schizophrenia patients. In most cases, abnormal SHANK3 genotype was also accompanied by cognitive disruptions. The present study queries whether common SHANK variants may also contribute to neuropsychological dysfunctions in schizophrenia. We genotyped five common coding or promoter variants located in SHANK1, SHANK2 and SHANK3. A comprehensive test battery was used to assess neuropsychological functions in 199 schizophrenia patients and 206 healthy control subjects. In addition, an independent sample of 77 subjects at risk for psychosis was analyzed for replication of significant findings. We found the T allele of the SHANK1 promoter variant rs3810280 to lead to significantly impaired auditory working memory as assessed with digit span (12.5 ± 3.6 vs. 14.8 ± 4.1, P < .001) in schizophrenia cases, applying strict Bonferroni correction for multiple testing. This finding was replicated for forward digit span in the at-risk sample (7.1 ± 2.0 vs. 8.3 ± 2.0, P = .044). Previously, altered memory functions and reduced dendritic spines and postsynaptic density of excitatory synapses were reported in SHANK1 knock-out mice. Moreover, the atypical neuroleptic clozapine was found to increase SHANK1 density in rats. Our findings suggest a role of SHANK1 in working memory deficits in schizophrenia, which may arise from neurodevelopmental changes to prefrontal cortical areas.
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- 2011
38. A coding variant of the novel serotonin receptor subunit 5-HT3E influences sustained attention in schizophrenia patients
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Joachim Klosterkötter, Wolfgang Wölwer, Leonhard Lennertz, Kai-Uwe Kühn, Ralf Pukrop, Michael Wagner, Marcella Rietschel, Wolfgang Maier, Rainald Mössner, Svenja Schulze-Rauschenbach, Ingo Frommann, Anna Schuhmacher, Wolfgang Gaebel, and Heinz Häfner
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Adult ,Male ,Genotype ,Protein subunit ,Neuropsychological Tests ,Serotonergic ,Polymorphism, Single Nucleotide ,Education ,Open Reading Frames ,medicine ,Humans ,Pharmacology (medical) ,Attention ,Receptor ,Gene ,Biological Psychiatry ,5-HT receptor ,Pharmacology ,Analysis of Variance ,Genetic Variation ,Middle Aged ,medicine.disease ,Psychiatry and Mental health ,Neurology ,Schizophrenia ,Endophenotype ,Female ,Schizophrenic Psychology ,Neurology (clinical) ,Serotonin ,Receptors, Serotonin, 5-HT3 ,Psychology ,Neuroscience ,Psychomotor Performance - Abstract
Sustained attention as measured by the Continuous Performance Test (CPT) has proved a valuable endophenotype for schizophrenia. Recently pharmacological studies suggested a role of the serotonin (5-HT) 3 receptor in schizophrenia. The 5-HT3 receptors are the only ligand-gated ion channels within the 5-HT receptor family. Applying an endophenotype approach, we investigated a potential impact of the genes of the 5-HT3A and 5-HT3B subunits as well as the novel 5-HT3C, 5-HT3D, and 5-HT3E subunits on CPT performance in subjects with schizophrenia. The study included 196 patients with schizophrenia, 113 of their parents, and 205 healthy controls recruited from community registers. Sustained attention was assessed with the Continuous Performance Test-Identical Pairs (CPT-IP). Assessing functional and coding variants of the 5-HT3 receptor subunit genes, we found the GG genotype of the 5-HT3E subunit gene (rs7627615; Thr86Ala) to be associated with better attentional capacities in subjects with schizophrenia and healthy controls. This study provides additional evidence for a role of the serotonergic system and the 5-HT3 receptor in schizophrenia.
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- 2009
39. Erratum: Genome-wide association study of obsessive-compulsive disorder
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Yi Wang, Nancy J. Cox, Sian M. J. Hemmings, Homero Vallada, Rianne M. Blom, Susanne Walitza, Euripedes Constantino Miguel, Christine Lochner, Peter Falkai, Margaret A. Richter, Eduardo Fournier, Danielle C. Cath, Christopher K. Edlund, M. A. Grados, Lauren M. McGrath, Michael A. Jenike, Patrick Evans, Jack Samuels, Michael H. Bloch, Jacquelyn Crane, Christopher Pittenger, Dan J. Stein, J.H. Smit, James F. Leckman, Richard Delorme, John Hardy, David L. Pauls, Donald W. Black, C. Illman, Danielle Posthuma, Mark A. Riddle, Amin Azzam, Beatriz Camarena, Leonhard Lennertz, Melissa Parkin, Carolina Cappi, Maria Cristina Cavallini, H.G.M. Westenberg, Lisa Osiecki, Paula Umaña, W. Maier, Jesen Fagerness, James A. Knowles, Michael Wagner, Jeremiah M. Scharf, Denise A. Chavira, Shaun Purcell, Anna Tikhomirov, Daniele Cusi, Marion Leboyer, Andrew B. Singleton, Francesca Frau, Abby J. Fyer, Chunyu Liu, H-J Grabe, James T. McCracken, Paul D. Arnold, Peter Heutink, Mark R. Cookson, J Veenstra-Vander Weele, M Conceição do Rosário, Anna Pluzhnikov, Michele T. Pato, Carol A. Mathews, Daniel B. Mirel, Rainald Moessner, James L. Kennedy, Andrew Crenshaw, Eric R. Gamazon, Jens R. Wendland, S. E. Stewart, Anuar Konkashbaev, Benjamin M. Neale, Stephan Ruhrmann, David V. Conti, Valsama Eapen, Humberto Nicolini, Karin Egberts, Dianne M. Hezel, Fabio Macciardi, Nuria Lanzagorta, Stephen A. Haddad, Carlos N. Pato, Benjamin D. Greenberg, Brooke Sheppard, Eric Strengman, David R. Rosenberg, Gregory L. Hanna, C. Mayerfeld, Bernadette Cullen, Aline S. Sampaio, Laura Bellodi, Helena Garrido, Dieter Deforce, F. Van Nieuwerburgh, Roel A. Ophoff, Gerald Nestadt, Dongmei Yu, D. Denys, E. Voyiaziakis, Maurizio Turiel, D. L. Murphy, Edwin H. Cook, Scott L. Rauch, Ana Gabriela Hounie, Vladimir Coric, Tobias J. Renner, Oscar J. Bienvenu, and J. R. Gibbs
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Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,medicine.medical_specialty ,Obsessive compulsive ,medicine ,Genome-wide association study ,Line (text file) ,Psychiatry ,Psychology ,Molecular Biology - Abstract
Correction to: Molecular Psychiatry advance online publication, 14 August 2012; doi:10.1038/mp.2012.85 The name of coauthor LK Davis was omitted from the author line. Dr Davis should have been listed as the tenth author (between ER Gamazon and L Osiecki). Her affiliation is as follows: Department ofMedicine, University of Chicago, Chicago, IL, USA.
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- 2013
40. The schizophrenia risk gene ZNF804A influences the antipsychotic response of positive schizophrenia symptoms
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Michael Wagner, Rainald Mössner, Marcella Rietschel, Wolfgang Maier, Boris B. Quednow, Leonhard Lennertz, Anja Steinbrecher, Anna Schuhmacher, Dan Rujescu, University of Zurich, and Mössner, R
- Subjects
Oncology ,Male ,medicine.medical_treatment ,Antipsychotic treatment ,2738 Psychiatry and Mental Health ,0302 clinical medicine ,2736 Pharmacology (medical) ,Pharmacology (medical) ,10064 Neuroscience Center Zurich ,0303 health sciences ,General Medicine ,Middle Aged ,Psychiatry and Mental health ,Treatment Outcome ,Schizophrenia ,10076 Center for Integrative Human Physiology ,Female ,Psychology ,2803 Biological Psychiatry ,Antipsychotic Agents ,Adult ,medicine.medical_specialty ,Genotype ,Kruppel-Like Transcription Factors ,Risk gene ,610 Medicine & health ,behavioral disciplines and activities ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Young Adult ,Sex Factors ,Internal medicine ,mental disorders ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,Psychiatry ,Antipsychotic ,Gene ,Biological Psychiatry ,030304 developmental biology ,medicine.disease ,Pharmacogenetics ,10054 Clinic for Psychiatry, Psychotherapy, and Psychosomatics ,Risk allele ,570 Life sciences ,biology ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Genetic factors determining the response to antipsychotic treatment in schizophrenia are poorly understood. A new schizophrenia susceptibility gene, the zinc-finger gene ZNF804A, has recently been identified. To assess the pharmacogenetic importance of this gene, we treated 144 schizophrenia patients and assessed the response of positive and negative symptoms by PANSS. Patients homozygous for the ZNF804A risk allele for schizophrenia (rs1344706 AA) showed poorer improvement of positive symptoms (7.35 ± 0.46) compared to patients with a protective allele (9.41 ± 0.71, P = 0.022). This provides further evidence that ZNF804A is of functional relevance to schizophrenia and indicates that ZNF804A may be a novel target for pharmacological interventions.
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