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Find video protocols related to scientific articles indexed in Pubmed.
Computerised assistance for ADHD testing is to be welcomed.
Nurs Stand
PUBLISHED: 11-20-2014
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A nursing team at Alder Hey Children's NHS Foundation Trust in Liverpool has introduced a computerised test into the assessment process for children and adolescents with attentional and behavioural difficulties (Features November 5).
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RCN faces challenges over rising inequalities within profession.
Nurs Stand
PUBLISHED: 08-14-2014
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It is difficult to understand why the RCN will not join colleagues in the Royal College of Midwives and other health unions in balloting members on industrial action (Editorial and News July 30). Is the RCN fearful of the outcome should the response be a yes?
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De novo CNVs in bipolar affective disorder and schizophrenia.
Hum. Mol. Genet.
PUBLISHED: 07-23-2014
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An increased rate of de novo copy number variants (CNVs) has been found in schizophrenia (SZ), autism and developmental delay. An increased rate has also been reported in bipolar affective disorder (BD). Here, in a larger BD sample, we aimed to replicate these findings and compare de novo CNVs between SZ and BD. We used Illumina microarrays to genotype 368 BD probands, 76 SZ probands and all their parents. Copy number variants were called by PennCNV and filtered for frequency (<1%) and size (>10 kb). Putative de novo CNVs were validated with the z-score algorithm, manual inspection of log R ratios (LRR) and qPCR probes. We found 15 de novo CNVs in BD (4.1% rate) and 6 in SZ (7.9% rate). Combining results with previous studies and using a cut-off of >100 kb, the rate of de novo CNVs in BD was intermediate between controls and SZ: 1.5% in controls, 2.2% in BD and 4.3% in SZ. Only the differences between SZ and BD and SZ and controls were significant. The median size of de novo CNVs in BD (448 kb) was also intermediate between SZ (613 kb) and controls (338 kb), but only the comparison between SZ and controls was significant. Only one de novo CNV in BD was in a confirmed SZ locus (16p11.2). Sporadic or early onset cases were not more likely to have de novo CNVs. We conclude that de novo CNVs play a smaller role in BD compared with SZ. Patients with a positive family history can also harbour de novo mutations.
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Genetic Risk for Schizophrenia: Convergence on Synaptic Pathways Involved in Plasticity.
Biol. Psychiatry
PUBLISHED: 07-18-2014
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Recent large-scale genomic studies have revealed two broad classes of risk alleles for schizophrenia: a polygenic component of risk mediated through multiple common risk variants and rarer more highly penetrant submicroscopic chromosomal deletions and duplications, known as copy number variants. The focus of this review is on the emerging findings from the latter and subsequent exome sequencing data of smaller, deleterious single nucleotide variants and indels. In these studies, schizophrenia patients were found to have enriched de novo mutations in genes belonging to the postsynaptic density at glutamatergic synapses, particularly components of the N-methyl-D-aspartate receptor signaling complex, including the PSD-95 complex, activity-regulated cytoskeleton-associated protein interactors, the fragile X mental retardation protein complex, voltage-gated calcium channels, and genes implicated in actin cytoskeletal dynamics. The convergence of these implicated genes onto a coherent biological pathway at the synapse, with a specific role in plasticity, provides a significant advance in understanding pathogenesis and points to new targets for biological investigation. We consider the implications of these studies in the context of existing genetic data and the potential need to reassess diagnostic boundaries of neuropsychiatric disorders before discussing ways forward for more directed mechanistic studies to develop stratified, novel therapeutic approaches in the future.
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SGCE and myoclonus dystonia: motor characteristics, diagnostic criteria and clinical predictors of genotype.
J. Neurol.
PUBLISHED: 06-17-2014
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Myoclonus dystonia syndrome (MDS) is a young-onset movement disorder. A proportion of cases are due to mutations in the maternally imprinted SGCE gene. We assembled the largest cohort of MDS patients to date, and determined the frequency and type of SGCE mutations. The aim was to establish the motor phenotype in mutation carriers and utility of current diagnostic criteria. Eighty-nine probands with clinical features compatible with MDS were recruited from the UK and Ireland. Patients were phenotypically classified as "definite", "probable" or "possible" MDS according to previous guidelines. SGCE was analyzed using direct sequencing and copy number variant analysis. In those where no mutation was found, DYT1 (GAG deletion), GCH1, THAP1 and NKX2.1 genes were also sequenced. Nineteen (21.3 %) probands had an SGCE mutation. Three patterns of motor symptoms emerged: (1) early childhood onset upper body myoclonus and dystonia, (2) early childhood onset lower limb dystonia, progressing later to more pronounced myoclonus and upper body involvement, and (3) later childhood onset upper body myoclonus and dystonia with evident cervical involvement. Five probands had large contiguous gene deletions ranging from 0.7 to 2.3 Mb in size with distinctive clinical features, including short stature, joint laxity and microcephaly. Our data confirms that SGCE mutations are most commonly identified in MDS patients with (1) age at onset ?10 years and (2) predominant upper body involvement of a pure myoclonus-dystonia. Cases with whole SGCE gene deletions had additional clinical characteristics, which are not always predicted by deletion size or gene involvement.
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Molecular ageing: free radical initiated epimerization of thymopentin--a case study.
J Chem Phys
PUBLISHED: 06-02-2014
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The epimerization of amino acid residues increases with age in living organisms. In the present study, the structural consequences and thermodynamic functions of the epimerization of thymopentin (TP-5), the active site of the thymic hormone thymopoietin, were studied using molecular dynamics and density functional theory methods. The results show that free radical-initiated D-amino acid formation is energetically favoured (-130 kJmol(-1)) for each residue and induces significant changes to the peptide structure. In comparison to the wild-type (each residue in the L-configuration), the radius of gyration of the D-Asp(3) epimer of the peptide decreased by 0.5 Å, and disrupted the intramolecular hydrogen bonding of the native peptide. Beyond establishing important structural, energetic and thermodynamic benchmarks and reference data for the structure of TP-5, these results disseminate the understanding of molecular ageing, the epimerization of amino acid residues.
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Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations.
, Jim van Os, Bart P Rutten, Inez Myin-Germeys, Philippe Delespaul, Wolfgang Viechtbauer, Catherine van Zelst, Richard Bruggeman, Ulrich Reininghaus, Craig Morgan, Robin M Murray, Marta Di Forti, Philip McGuire, Lucia R Valmaggia, Matthew J Kempton, Charlotte Gayer-Anderson, Kathryn Hubbard, Stephanie Beards, Simona A Stilo, Adanna Onyejiaka, François Bourque, Gemma Modinos, Stefania Tognin, Maria Calem, Michael C O'Donovan, Michael J Owen, Peter Holmans, Nigel Williams, Nicholas Craddock, Alexander Richards, Isla Humphreys, Andreas Meyer-Lindenberg, F Markus Leweke, Heike Tost, Ceren Akdeniz, Cathrin Rohleder, J Malte Bumb, Emanuel Schwarz, Koksal Alptekin, Alp Üçok, Meram Can Saka, E Cem Atbaşoğlu, Sinan Guloksuz, Güvem Gümüş-Akay, Burçin Cihan, Hasan Karadag, Haldan Soygür, Eylem Şahin Cankurtaran, Semra Ulusoy, Berna Akdede, Tolga Binbay, Ahmet Ayer, Handan Noyan, Gülşah Karadayı, Elçin Akturan, Halis Ulas, Celso Arango, Mara Parellada, Miguel Bernardo, Julio Sanjuan, Julio Bobes, Manuel Arrojo, Jose Luis Santos, Pedro Cuadrado, José Juan Rodríguez Solano, Angel Carracedo, Enrique García Bernardo, Laura Roldán, Gonzalo Lopez, Bibiana Cabrera, Sabrina Cruz, Eva Ma Díaz Mesa, María Pouso, Estela Jiménez, Teresa Sanchez, Marta Rapado, Emiliano González, Covadonga Martínez, Emilio Sanchez, Ma Soledad Olmeda, Lieuwe de Haan, Eva Velthorst, Mark van der Gaag, Jean-Paul Selten, Daniella van Dam, Elsje van der Ven, Floor van der Meer, Elles Messchaert, Tamar Kraan, Nadine Burger, Marion Leboyer, Andrei Szoke, Franck Schürhoff, Pierre-Michel Llorca, Stéphane Jamain, Andrea Tortelli, Flora Frijda, Jeanne Vilain, Anne-Marie Galliot, Grégoire Baudin, Aziz Ferchiou, Jean-Romain Richard, Ewa Bulzacka, Thomas Charpeaud, Anne-Marie Tronche, Marc De Hert, Ruud van Winkel, Jeroen Decoster, Catherine Derom, Evert Thiery, Nikos C Stefanis, Gabriele Sachs, Harald Aschauer, Iris Lasser, Bernadette Winklbaur, Monika Schlögelhofer, Anita Riecher-Rossler, Stefan Borgwardt, Anna Walter, Fabienne Harrisberger, Renata Smieskova, Charlotte Rapp, Sarah Ittig, Fabienne Soguel-dit-Piquard, Erich Studerus, Joachim Klosterkötter, Stephan Ruhrmann, Julia Paruch, Dominika Julkowski, Desiree Hilboll, Pak C Sham, Stacey S Cherny, Eric Y H Chen, Desmond D Campbell, Miaoxin Li, Carlos María Romeo-Casabona, Aitziber Emaldi Cirión, Asier Urruela Mora, Peter Jones, James Kirkbride, Mary Cannon, Dan Rujescu, Ilaria Tarricone, Domenico Berardi, Elena Bonora, Marco Seri, Thomas Marcacci, Luigi Chiri, Federico Chierzi, Viviana Storbini, Mauro Braca, Maria Gabriella Minenna, Ivonne Donegani, Angelo Fioritti, Daniele La Barbera, Caterina Erika La Cascia, Alice Mulè, Lucia Sideli, Rachele Sartorio, Laura Ferraro, Giada Tripoli, Fabio Seminerio, Anna Maria Marinaro, Patrick McGorry, Barnaby Nelson, G Paul Amminger, Christos Pantelis, Paulo R Menezes, Cristina M Del-Ben, Silvia H Gallo Tenan, Rosana Shuhama, Mirella Ruggeri, Sarah Tosato, Antonio Lasalvia, Chiara Bonetto, Elisa Ira, Merete Nordentoft, Marie-Odile Krebs, Neus Barrantes-Vidal, Paula Cristóbal, Thomas R Kwapil, Elisa Brietzke, Rodrigo A Bressan, Ary Gadelha, Nadja P Maric, Sanja Andric, Marina Mihaljevic, Tijana Mirjanic.
Schizophr Bull
PUBLISHED: 05-24-2014
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Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype.
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Synaptic, transcriptional and chromatin genes disrupted in autism.
Silvia De Rubeis, Xin He, Arthur P Goldberg, Christopher S Poultney, Kaitlin Samocha, A Ercument Cicek, Yan Kou, Li Liu, Menachem Fromer, Susan Walker, Tarjinder Singh, Lambertus Klei, Jack Kosmicki, Shih-Chen Fu, Branko Aleksic, Monica Biscaldi, Patrick F Bolton, Jessica M Brownfeld, Jinlu Cai, Nicholas G Campbell, Angel Carracedo, Maria H Chahrour, Andreas G Chiocchetti, Hilary Coon, Emily L Crawford, Lucy Crooks, Sarah R Curran, Geraldine Dawson, Eftichia Duketis, Bridget A Fernandez, Louise Gallagher, Evan Geller, Stephen J Guter, R Sean Hill, Iuliana Ionita-Laza, Patricia Jimenez Gonzalez, Helena Kilpinen, Sabine M Klauck, Alexander Kolevzon, Irene Lee, Jing Lei, Terho Lehtimäki, Chiao-Feng Lin, Avi Ma'ayan, Christian R Marshall, Alison L McInnes, Benjamin Neale, Michael J Owen, Norio Ozaki, Mara Parellada, Jeremy R Parr, Shaun Purcell, Kaija Puura, Deepthi Rajagopalan, Karola Rehnström, Abraham Reichenberg, Aniko Sabo, Michael Sachse, Stephan J Sanders, Chad Schafer, Martin Schulte-Rüther, David Skuse, Christine Stevens, Peter Szatmari, Kristiina Tammimies, Otto Valladares, Annette Voran, Li-San Wang, Lauren A Weiss, A Jeremy Willsey, Timothy W Yu, Ryan K C Yuen, , Edwin H Cook, Christine M Freitag, Michael Gill, Christina M Hultman, Thomas Lehner, Aarno Palotie, Gerard D Schellenberg, Pamela Sklar, Matthew W State, James S Sutcliffe, Christopher A Walsh, Stephen W Scherer, Michael E Zwick, Jeffrey C Barrett, David J Cutler, Kathryn Roeder, Bernie Devlin, Mark J Daly, Joseph D Buxbaum.
Nature
PUBLISHED: 05-18-2014
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The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
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Relationship between obesity and the risk of clinically significant depression: Mendelian randomisation study.
Br J Psychiatry
PUBLISHED: 05-08-2014
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Obesity has been shown to be associated with depression and it has been suggested that higher body mass index (BMI) increases the risk of depression and other common mental disorders. However, the causal relationship remains unclear and Mendelian randomisation, a form of instrumental variable analysis, has recently been employed to attempt to resolve this issue.
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Exploring the indirect effects of catechol-O-methyltransferase (COMT) genotype on psychotic experiences through cognitive function and anxiety disorders in a large birth cohort of children.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 05-05-2014
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Children reporting psychotic experiences (PEs) are at increased risk of developing psychosis in adulthood. Cognitive deficits and anxiety disorders often precede psychotic disorders and are associated with higher risk of PEs. While the high activity alleles of variants within COMT have been associated with cognitive deficits, and the low activity alleles with higher risk of anxiety disorders, no associations of COMT with PEs have been found. One possible explanation is that the association between COMT and PEs is indirect, through cognitive function and anxiety disorders. We examined whether the association between PEs and COMT (four single nucleotide polymorphisms and three haplotypes) is indirect, through cognition or anxiety disorders. 6,784 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC) were genotyped and completed neurocognitive assessments at ages 8 and 11, as well as semi-structured interviews for anxiety disorders and PEs at ages 10 and 12, respectively. Alleles rs2097603 and rs4680, and two COMT haplotypes, all indexing high activity, were indirectly associated with higher risk of PEs through impaired processing speed, IQ and attention. There was no evidence of a total effect of COMT on PEs, nor for an indirect effect through anxiety disorders. This is the first study to examine indirect effects of COMT on PEs. Evidence of an indirect association suggests a complex developmental pathway underlies the emergence of PEs in children, with possible implications for prevention/intervention strategies. Our findings provide additional support for processing speed and attention as endophenotypes in psychotic disorders.
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The synapse in schizophrenia.
Eur. J. Neurosci.
PUBLISHED: 04-10-2014
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It has been several decades since synaptic dysfunction was first suggested to play a role in schizophrenia, but only in the last few years has convincing evidence been obtained as progress has been made in elucidating the genetic underpinnings of the disorder. In the intervening years much has been learned concerning the complex macromolecular structure of the synapse itself, and genetic studies are now beginning to draw upon these advances. Here we outline our current understanding of the genetic architecture of schizophrenia and examine the evidence for synaptic involvement. A strong case can now be made that disruption of glutamatergic signalling pathways regulating synaptic plasticity contributes to the aetiology of schizophrenia.
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Biological overlap of attention-deficit/hyperactivity disorder and autism spectrum disorder: evidence from copy number variants.
J Am Acad Child Adolesc Psychiatry
PUBLISHED: 03-24-2014
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Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur and share genetic risks. The aim of this analysis was to determine more broadly whether ADHD and ASD share biological underpinnings.
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The Research Domain Criteria: moving the goalposts to change the game.
Br J Psychiatry
PUBLISHED: 03-05-2014
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There is increasing concern that a reliance on the descriptive, syndrome-based diagnostic criteria of ICD and DSM is impeding progress in research. The USA's major funder of psychiatric research, the National Institute of Mental Health (NIMH), have stated their intention to encourage more research across diagnostic categories using a novel framework based on findings in neuroscience.
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Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome.
Am J Psychiatry
PUBLISHED: 03-01-2014
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Chromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge the first large-scale collaborative study of rates and sex distributions of psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. The associations among psychopathology, intellect, and functioning were examined in a subgroup of participants.
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Genetic relationships between schizophrenia, bipolar disorder, and schizoaffective disorder.
Schizophr Bull
PUBLISHED: 02-24-2014
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There is substantial evidence for partial overlap of genetic influences on schizophrenia and bipolar disorder, with family, twin, and adoption studies showing a genetic correlation between the disorders of around 0.6. Results of genome-wide association studies are consistent with commonly occurring genetic risk variants, contributing to both the shared and nonshared aspects, while studies of large, rare chromosomal structural variants, particularly copy number variants, show a stronger influence on schizophrenia than bipolar disorder to date. Schizoaffective disorder has been less investigated but shows substantial familial overlap with both schizophrenia and bipolar disorder. A twin analysis is consistent with genetic influences on schizoaffective episodes being entirely shared with genetic influences on schizophrenic and manic episodes, while association studies suggest the possibility of some relatively specific genetic influences on broadly defined schizoaffective disorder, bipolar subtype. Further insights into genetic relationships between these disorders are expected as studies continue to increase in sample size and in technical and analytical sophistication, information on phenotypes beyond clinical diagnoses are increasingly incorporated, and approaches such as next-generation sequencing identify additional types of genetic risk variant.
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Benchmark study on glyphosate-resistant crop systems in the United States. Economics of herbicide resistance management practices in a 5 year field-scale study.
Pest Manag. Sci.
PUBLISHED: 02-02-2014
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Since the introduction of glyphosate-resistant (GR) crops, growers have often relied on glyphosate-only weed control programs. As a result, multiple weeds have evolved resistance to glyphosate. A 5 year study including 156 growers from Illinois, Iowa, Indiana, Nebraska, North Carolina and Mississippi in the United States was conducted to compare crop yields and net returns between grower standard weed management programs (SPs) and programs containing best management practices (BMPs) recommended by university weed scientists. The BMPs were designed to prevent or mitigate/manage evolved herbicide resistance.
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De novo mutations in schizophrenia implicate synaptic networks.
Nature
PUBLISHED: 01-22-2014
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Inherited alleles account for most of the genetic risk for schizophrenia. However, new (de novo) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here we show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose messenger RNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case-control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders.
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Genetic relationships between suicide attempts, suicidal ideation and major psychiatric disorders: a genome-wide association and polygenic scoring study.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 01-20-2014
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Epidemiological studies have recognized a genetic diathesis for suicidal behavior, which is independent of other psychiatric disorders. Genome-wide association studies (GWAS) on suicide attempt (SA) and ideation have failed to identify specific genetic variants. Here, we conduct further GWAS and for the first time, use polygenic score analysis in cohorts of patients with mood disorders, to test for common genetic variants for mood disorders and suicide phenotypes. Genome-wide studies for SA were conducted in the RADIANT and GSK-Munich recurrent depression samples and London Bipolar Affective Disorder Case-Control Study (BACCs) then meta-analysis was performed. A GWAS on suicidal ideation during antidepressant treatment had previously been conducted in the Genome Based Therapeutic Drugs for Depression (GENDEP) study. We derived polygenic scores from each sample and tested their ability to predict SA in the mood disorder cohorts or ideation status in the GENDEP study. Polygenic scores for major depressive disorder, bipolar disorder and schizophrenia from the Psychiatric Genomics Consortium were used to investigate pleiotropy between psychiatric disorders and suicide phenotypes. No significant evidence for association was detected at any SNP in GWAS or meta-analysis. Polygenic scores for major depressive disorder significantly predicted suicidal ideation in the GENDEP pharmacogenetics study and also predicted SA in a combined validation dataset. Polygenic scores for SA showed no predictive ability for suicidal ideation. Polygenic score analysis suggests pleiotropy between psychiatric disorders and suicidal ideation whereas the tendency to act on such thoughts may have a partially independent genetic diathesis.
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Further evidence for high rates of schizophrenia in 22q11.2 deletion syndrome.
Schizophr. Res.
PUBLISHED: 01-19-2014
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22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of psychotic disorder, particularly schizophrenia. The deletion is considered to be a biological model for understanding this debilitating psychiatric disorder. It is unclear whether the psychotic manifestations in 22q11.2DS are similar to those in schizophrenia patients without the deletion. Catechol-O-methyltransferase (COMT), a positional candidate gene for schizophrenia, resides within the 22q11.2 region. It remains unknown whether hemizygosity for this gene is associated with risk of psychotic disorder. This study includes 83 adults with 22q11.2DS, 90 non-deleted individuals with schizophrenia, and 316 normal controls. Psychopathology was assessed using the Schedules for Clinical Assessment in Neuropsychiatry, the Schedules for the Assessment of Positive and Negative Symptoms and the Global Assessment Scale. Schizotypy was assessed with the Kings Schizotypy Questionnaire and Oxford Liverpool Inventory of Feelings and Emotions. IQ estimates were also obtained. Adults with 22q11.2DS were genotyped for a number of COMT polymorphisms as well as the Ashkenazi risk haplotype. This study confirms high rates of psychotic disorder (29%) in individuals with 22q11.2DS of which the majority had schizophrenia (22%). There does not appear to be a differential expression of schizophrenic symptom clusters in 22q11.2DS in relation to sporadic schizophrenia, though schizophrenia in 22q11.2DS seems to be less severe in terms of global assessment scores. Psychosis proneness seems to be of genetic origin in 22q11.2DS as individuals with 22q11.2DS without schizophrenia had higher schizotypy scores than normal controls. Finally, COMT was not associated with schizophrenia status or schizotypy.
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Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery.
Nat. Biotechnol.
PUBLISHED: 01-15-2014
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If immunized with an antigen of interest, transgenic mice with large portions of unrearranged human immunoglobulin loci can produce fully human antigen-specific antibodies; several such antibodies are in clinical use. However, technical limitations inherent to conventional transgenic technology and sequence divergence between the human and mouse immunoglobulin constant regions limit the utility of these mice. Here, using repetitive cycles of genome engineering in embryonic stem cells, we have inserted the entire human immunoglobulin variable-gene repertoire (2.7 Mb) into the mouse genome, leaving the mouse constant regions intact. These transgenic mice are viable and fertile, with an immune system resembling that of wild-type mice. Antigen immunization results in production of high-affinity antibodies with long human-like complementarity-determining region 3 (CDR3H), broad epitope coverage and strong signatures of somatic hypermutation. These mice provide a robust system for the discovery of therapeutic human monoclonal antibodies; as a surrogate readout of the human antibody response, they may also aid vaccine design efforts.
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Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice.
Genome Med
PUBLISHED: 01-01-2014
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Psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder, attention-deficit/hyperactivity disorder and autism spectrum disorder are common and result in significant morbidity and mortality. Although currently classified into distinct disorder categories, they show clinical overlap and familial co-aggregation, and share genetic risk factors. Recent advances in psychiatric genomics have provided insight into the potential mechanisms underlying the overlap between these disorders, implicating genes involved in neurodevelopment, synaptic plasticity, learning and memory. Furthermore, evidence from copy number variant, exome sequencing and genome-wide association studies supports a gradient of neurodevelopmental psychopathology indexed by mutational load or mutational severity, and cognitive impairment. These findings have important implications for psychiatric research, highlighting the need for new approaches to stratifying patients for research. They also point the way for work aiming to advance our understanding of the pathways from genotype to clinical phenotype, which will be required in order to inform new classification systems and to develop novel therapeutic strategies.
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Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.
Valentina Escott-Price, Celine Bellenguez, Li-San Wang, Seung-Hoan Choi, Denise Harold, Lesley Jones, Peter Holmans, Amy Gerrish, Alexey Vedernikov, Alexander Richards, Anita L Destefano, Jean-Charles Lambert, Carla A Ibrahim-Verbaas, Adam C Naj, Rebecca Sims, Gyungah Jun, Joshua C Bis, Gary W Beecham, Benjamin Grenier-Boley, Giancarlo Russo, Tricia A Thornton-Wells, Nicola Denning, Albert V Smith, Vincent Chouraki, Charlene Thomas, M Arfan Ikram, Diana Zelenika, Badri N Vardarajan, Yoichiro Kamatani, Chiao-Feng Lin, Helena Schmidt, Brian Kunkle, Melanie L Dunstan, Maria Vronskaya, , Andrew D Johnson, Agustin Ruíz, Marie-Therese Bihoreau, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Olivier Hanon, Annette L Fitzpatrick, Joseph D Buxbaum, Dominique Campion, Paul K Crane, Clinton Baldwin, Tim Becker, Vilmundur Gudnason, Carlos Cruchaga, David Craig, Najaf Amin, Claudine Berr, Oscar L Lopez, Philip L De Jager, Vincent Deramecourt, Janet A Johnston, Denis Evans, Simon Lovestone, Luc Letenneur, Isabel Hernández, David C Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M Goate, Nathalie Fiévet, Matthew J Huentelman, Michael Gill, Kristelle Brown, M Ilyas Kamboh, Lina Keller, Pascale Barberger-Gateau, Bernadette McGuinness, Eric B Larson, Amanda J Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, Ekaterina Rogaeva, John Gallacher, Peter St George-Hyslop, Jordi Clarimón, Alberto Lleó, Anthony Bayer, Debby W Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petra Proitsi, John Collinge, Sandro Sorbi, Florentino Sanchez Garcia, Nick C Fox, John Hardy, Maria Candida Deniz Naranjo, Paolo Bosco, Robert Clarke, Carol Brayne, Daniela Galimberti, Elio Scarpini, Ubaldo Bonuccelli, Michelangelo Mancuso, Gabriele Siciliano, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, Ana Frank-García, Francesco Panza, Vincenzo Solfrizzi, Paolo Caffarra, Benedetta Nacmias, William Perry, Manuel Mayhaus, Lars Lannfelt, Hakon Hakonarson, Sabrina Pichler, Minerva M Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alvarez, Fanggeng Zou, Otto Valladares, Steven G Younkin, Eliecer Coto, Kara L Hamilton-Nelson, Wei Gu, Cristina Razquin, Pau Pastor, Ignacio Mateo, Michael J Owen, Kelley M Faber, Palmi V Jonsson, Onofre Combarros, Michael C O'Donovan, Laura B Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas H Mosley, David A Bennett, Tamara B Harris, Laura Fratiglioni, Clive Holmes, Renée F A G de Bruijn, Peter Passmore, Thomas J Montine, Karolien Bettens, Jerome I Rotter, Alexis Brice, Kevin Morgan, Tatiana M Foroud, Walter A Kukull, Didier Hannequin, John F Powell, Michael A Nalls, Karen Ritchie, Kathryn L Lunetta, John S K Kauwe, Eric Boerwinkle, Matthias Riemenschneider, Mercè Boada, Mikko Hiltunen, Eden R Martin, Reinhold Schmidt, Dan Rujescu, Jean-Francois Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus M Nöthen, Caroline Graff, Bruce M Psaty, Jonathan L Haines, Mark Lathrop, Margaret A Pericak-Vance, Lenore J Launer, Christine Van Broeckhoven, Lindsay A Farrer, Cornelia M van Duijn, Alfredo Ramírez, Sudha Seshadri, Gerard D Schellenberg, Philippe Amouyel, Julie Williams.
PLoS ONE
PUBLISHED: 01-01-2014
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Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
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Care would have improved long ago if nurses warnings had been heeded.
Nurs Stand
PUBLISHED: 12-12-2013
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We owe much to nursing hero Graham Pink (Features November 20, Letters December 4), and to all the whistleblowers who have put their careers and lives on the line to highlight poor standards of patient care.
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Analysis of copy number variations at 15 schizophrenia-associated loci.
Br J Psychiatry
PUBLISHED: 12-05-2013
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A number of copy number variants (CNVs) have been suggested as susceptibility factors for schizophrenia. For some of these the data remain equivocal, and the frequency in individuals with schizophrenia is uncertain.
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Where are the unions when it comes to whistleblowing?
Nurs Stand
PUBLISHED: 12-05-2013
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Rachel Potter (Letters November 13) asks what should nurses do when they have reported instances of unsafe staffing to managers and their concerns have been ignored?
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A Population-Based Study of Genetic Variation and Psychotic Experiences in Adolescents.
Schizophr Bull
PUBLISHED: 10-30-2013
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Psychotic experiences are not uncommon in general population samples, but no studies have examined to what extent confirmed risk variants for schizophrenia are associated with such experiences. A total of 3483 children in a birth cohort study participated in semistructured interviews for psychotic experiences at ages 12 and 18. We examined whether (1) a composite measure of risk for schizophrenia conferred by common alleles (polygenic score) was associated with psychotic experiences, (2) variants with genome-wide evidence for association with schizophrenia were associated with psychotic experiences, and (3) we could identify genetic variants for psychotic experiences using a genome-wide association (GWA) approach. We found no evidence that a schizophrenia polygenic score, or variants showing genome-wide evidence of association with schizophrenia, were associated with adolescent psychotic experiences within the general population. In fact, individuals who had a higher number of risk alleles for genome-wide hits for schizophrenia showed a decreased risk of psychotic experiences. In the GWA study, no variants showed GWA for psychotic experiences, and there was no evidence that the strongest hits (P < 5 × 10(-5)) were enriched for variants associated with schizophrenia in large consortia. Although polygenic scores are weak tools for prediction of schizophrenia, they show strong evidence of association with this disorder. Our findings, however, lend little support to the hypothesis that psychotic experiences in population-based samples of adolescents share a comparable genetic architecture to schizophrenia, or that utilizing a broader and more common phenotype of psychotic experiences will be an efficient approach to increase understanding of the genetic etiology of schizophrenia.
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CNV analysis in a large schizophrenia sample implicates deletions at 16p12.1 and SLC1A1 and duplications at 1p36.33 and CGNL1.
Hum. Mol. Genet.
PUBLISHED: 10-26-2013
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Large and rare copy number variants (CNVs) at several loci have been shown to increase risk for schizophrenia. Aiming to discover novel susceptibility CNV loci, we analyzed 6882 cases and 11 255 controls genotyped on Illumina arrays, most of which have not been used for this purpose before. We identified genes enriched for rare exonic CNVs among cases, and then attempted to replicate the findings in additional 14 568 cases and 15 274 controls. In a combined analysis of all samples, 12 distinct loci were enriched among cases with nominal levels of significance (P < 0.05); however, none would survive correction for multiple testing. These loci include recurrent deletions at 16p12.1, a locus previously associated with neurodevelopmental disorders (P = 0.0084 in the discovery sample and P = 0.023 in the replication sample). Other plausible candidates include non-recurrent deletions at the glutamate transporter gene SLC1A1, a CNV locus recently suggested to be involved in schizophrenia through linkage analysis, and duplications at 1p36.33 and CGNL1. A burden analysis of large (>500 kb), rare CNVs showed a 1.2% excess in cases after excluding known schizophrenia-associated loci, suggesting that additional susceptibility loci exist. However, even larger samples are required for their discovery.
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Psychopathology and cognition in children with 22q11.2 deletion syndrome.
Br J Psychiatry
PUBLISHED: 10-10-2013
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Children with 22q11.2 deletion syndrome (22q11.2DS) have been reported to have high rates of cognitive and psychiatric problems.
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Reduced burden of very large and rare CNVs in bipolar affective disorder.
Bipolar Disord
PUBLISHED: 08-15-2013
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Large, rare chromosomal copy number variants (CNVs) have been shown to increase the risk for schizophrenia and other neuropsychiatric disorders including autism, attention-deficit hyperactivity disorder, learning difficulties, and epilepsy. Their role in bipolar disorder (BD) is less clear. There are no reports of an increase in large, rare CNVs in BD in general, but some have reported an increase in early-onset cases. We previously found that the rate of such CNVs in individuals with BD was not increased, even in early-onset cases. Our aim here was to examine the rate of large rare CNVs in BD in comparison with a new large independent reference sample from the same country.
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Analysis of Genome-Wide Association Studies of Alzheimer Disease and of Parkinson Disease to Determine If These 2 Diseases Share a Common Genetic Risk.
JAMA Neurol
PUBLISHED: 08-08-2013
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IMPORTANCE Despite Alzheimer disease (AD) and Parkinson disease (PD) being clinically distinct entities, there is a possibility of a pathological overlap, with some genome-wide association (GWA) studies suggesting that the 2 diseases represent a biological continuum. The application of GWA studies to idiopathic forms of AD and PD have identified a number of loci that contain genetic variants that increase the risk of these disorders. OBJECTIVE To assess the genetic overlap between PD and AD by testing for the presence of potentially pleiotropic loci in 2 recent GWA studies of PD and AD. DESIGN Combined GWA analysis. SETTING Data sets from the United Kingdom, Germany, France, and the United States. PARTICIPANTS Thousands of patients with AD or PD and their controls. MAIN OUTCOMES AND MEASURES Meta-analysis of GWA studies of AD and PD. METHODS To identify evidence for potentially pleiotropic alleles that increased the risk for both PD and AD, we performed a combined PD-AD meta-analysis and compared the results with those obtained in the primary GWA studies. We also tested for a net effect of potentially polygenic alleles that were shared by both disorders by performing a polygenic score analysis. Finally, we also performed a gene-based association analysis that was aimed at detecting genes that harbor multiple disease-causing single-nucleotide polymorphisms, some of which confer a risk of PD and some a risk of AD. RESULTS Detailed interrogation of the single-nucleotide polymorphism, polygenic, and gene-based analyses resulted in no significant evidence that supported the presence of loci that increase the risk of both PD and AD. CONCLUSIONS AND RELEVANCE Our findings therefore imply that loci that increase the risk of both PD and AD are not widespread and that the pathological overlap could instead be "downstream" of the primary susceptibility genes that increase the risk of each disease.
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The role of the major histocompatibility complex region in cognition and brain structure: a schizophrenia GWAS follow-up.
Am J Psychiatry
PUBLISHED: 08-02-2013
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OBJECTIVE The authors investigated the effects of recently identified genome-wide significant schizophrenia genetic risk variants on cognition and brain structure. METHOD A panel of six single-nucleotide polymorphisms (SNPs) was selected to represent genome-wide significant loci from three recent genome-wide association studies (GWAS) for schizophrenia and was tested for association with cognitive measures in 346 patients with schizophrenia and 2,342 healthy comparison subjects. Nominally significant results were evaluated for replication in an independent case-control sample. For SNPs showing evidence of association with cognition, associations with brain structural volumes were investigated in a large independent healthy comparison sample. RESULTS Five of the six SNPs showed no significant association with any cognitive measure. One marker in the major histocompatibility complex (MHC) region, rs6904071, showed independent, replicated evidence of association with delayed episodic memory and was significant when both samples were combined. In the combined sample of up to 3,100 individuals, this SNP was associated with widespread effects across cognitive domains, although these additional associations were no longer significant after adjusting for delayed episodic memory. In the large independent structural imaging sample, the same SNP was also associated with decreased hippocampal volume. CONCLUSIONS The authors identified a SNP in the MHC region that was associated with cognitive performance in patients with schizophrenia and healthy comparison subjects. This SNP, rs6904071, showed a replicated association with episodic memory and hippocampal volume. These findings implicate the MHC region in hippocampal structure and functioning, consistent with the role of MHC proteins in synaptic development and function. Follow-up of these results has the potential to provide insights into the pathophysiology of schizophrenia and cognition.
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Genome-wide association analysis identifies 13 new risk loci for schizophrenia.
Stephan Ripke, Colm O'Dushlaine, Kimberly Chambert, Jennifer L Moran, Anna K Kähler, Susanne Akterin, Sarah E Bergen, Ann L Collins, James J Crowley, Menachem Fromer, Yunjung Kim, Sang Hong Lee, Patrik K E Magnusson, Nick Sanchez, Eli A Stahl, Stephanie Williams, Naomi R Wray, Kai Xia, Francesco Bettella, Anders D Borglum, Brendan K Bulik-Sullivan, Paul Cormican, Nick Craddock, Christiaan de Leeuw, Naser Durmishi, Michael Gill, Vera Golimbet, Marian L Hamshere, Peter Holmans, David M Hougaard, Kenneth S Kendler, Kuang Lin, Derek W Morris, Ole Mors, Preben B Mortensen, Benjamin M Neale, Francis A O'Neill, Michael J Owen, Milica Pejović Milovančević, Danielle Posthuma, John Powell, Alexander L Richards, Brien P Riley, Douglas Ruderfer, Dan Rujescu, Engilbert Sigurdsson, Teimuraz Silagadze, August B Smit, Hreinn Stefansson, Stacy Steinberg, Jaana Suvisaari, Sarah Tosato, Matthijs Verhage, James T Walters, , Douglas F Levinson, Pablo V Gejman, Claudine Laurent, Bryan J Mowry, Michael C O'Donovan, Ann E Pulver, Sibylle G Schwab, Dieter B Wildenauer, Frank Dudbridge, Jianxin Shi, Margot Albus, Madeline Alexander, Dominique Campion, David Cohen, Dimitris Dikeos, Jubao Duan, Peter Eichhammer, Stephanie Godard, Mark Hansen, F Bernard Lerer, Kung-Yee Liang, Wolfgang Maier, Jacques Mallet, Deborah A Nertney, Gerald Nestadt, Nadine Norton, George N Papadimitriou, Robert Ribble, Alan R Sanders, Jeremy M Silverman, Dermot Walsh, Nigel M Williams, Brandon Wormley, Maria J Arranz, Steven Bakker, Stephan Bender, Elvira Bramon, David Collier, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Assen Jablensky, René S Kahn, Luba Kalaydjieva, Stephen Lawrie, Cathryn M Lewis, Don H Linszen, Ignacio Mata, Andrew McIntosh, Robin M Murray, Roel A Ophoff, Jim van Os, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Peter Donnelly, Inês Barroso, Jenefer M Blackwell, Matthew A Brown, Juan P Casas, Aiden P Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S Markus, Christopher G Mathew, Colin N A Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Richard C Trembath, Ananth C Viswanathan, Nicholas W Wood, Chris C A Spencer, Gavin Band, Celine Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard D Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Sarah E Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew J Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Mark I McCarthy, Kari Stefansson, Edward Scolnick, Shaun Purcell, Steven A McCarroll, Pamela Sklar, Christina M Hultman, Patrick F Sullivan.
Nat. Genet.
PUBLISHED: 08-01-2013
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Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
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Investigating the genetic variation underlying episodicity in major depressive disorder: Suggestive evidence for a bipolar contribution.
J Affect Disord
PUBLISHED: 06-29-2013
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Highly recurrent major depressive disorder (MDD) has reportedly increased risk of shifting to bipolar disorder; high recurrence frequency has, therefore, featured as evidence of soft bipolarity. We aimed to investigate the genetic underpinnings of total depressive episode count in recurrent MDD.
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Shared polygenic contribution between childhood attention-deficit hyperactivity disorder and adult schizophrenia.
Br J Psychiatry
PUBLISHED: 05-23-2013
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There is recent evidence of some degree of shared genetic susceptibility between adult schizophrenia and childhood attention-deficit hyperactivity disorder (ADHD) for rare chromosomal variants.
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The Penetrance of Copy Number Variations for Schizophrenia and Developmental Delay.
Biol. Psychiatry
PUBLISHED: 05-13-2013
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Several recurrent copy number variants (CNVs) have been shown to increase the risk of developing schizophrenia (SCZ), developmental delay (DD), autism spectrum disorders (ASD), and various congenital malformations (CM). Their penetrance for SCZ has been estimated to be modest. However, comparisons between their penetrance for SCZ or DD/ASD/CM, or estimates of the total penetrance for any of these disorders have not yet been made.
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Reciprocal Duplication of the Williams-Beuren Syndrome Deletion on Chromosome 7q11.23 Is Associated with Schizophrenia.
Biol. Psychiatry
PUBLISHED: 05-03-2013
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Several copy number variants (CNVs) have been implicated as susceptibility factors for schizophrenia (SZ). Some of these same CNVs also increase risk for autism spectrum disorders, suggesting an etiologic overlap between these conditions. Recently, de novo duplications of a region on chromosome 7q11.23 were associated with autism spectrum disorders. The reciprocal deletion of this region causes Williams-Beuren syndrome.
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Defective processing speed and nonclinical psychotic experiences in children: longitudinal analyses in a large birth cohort.
Am J Psychiatry
PUBLISHED: 05-02-2013
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Psychotic experiences in children are associated with an elevated risk of developing psychosis. The authors investigated whether the pattern of cognitive deficits present in psychosis also exists in children with psychotic experiences within the general population.
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High loading of polygenic risk for ADHD in children with comorbid aggression.
Am J Psychiatry
PUBLISHED: 04-20-2013
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OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.
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Definition and description of schizophrenia in the DSM-5.
Schizophr. Res.
PUBLISHED: 03-29-2013
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Although dementia praecox or schizophrenia has been considered a unique disease for over a century, its definitions and boundaries have changed over this period and its etiology and pathophysiology remain elusive. Despite changing definitions, DSM-IV schizophrenia is reliably diagnosed, has fair validity and conveys useful clinical information. Therefore, the essence of the broad DSM-IV definition of schizophrenia is retained in DSM-5. The clinical manifestations are extremely diverse, however, with this heterogeneity being poorly explained by the DSM-IV clinical subtypes and course specifiers. Additionally, the boundaries of schizophrenia are imprecisely demarcated from schizoaffective disorder and other diagnostic categories and its special emphasis on Schneiderian "first-rank" symptoms appears misplaced. Changes in the definition of schizophrenia in DSM-5 seek to address these shortcomings and incorporate the new information about the nature of the disorder accumulated over the past two decades. Specific changes in its definition include elimination of the classic subtypes, addition of unique psychopathological dimensions, clarification of cross-sectional and longitudinal course specifiers, elimination of special treatment of Schneiderian first-rank symptoms, better delineation of schizophrenia from schizoaffective disorder, and clarification of the relationship of schizophrenia to catatonia. These changes should improve diagnosis and characterization of individuals with schizophrenia and facilitate measurement-based treatment and concurrently provide a more useful platform for research that will elucidate its nature and permit a more precise future delineation of the schizophrenias.
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The interaction between child maltreatment, adult stressful life events and the 5-HTTLPR in major depression.
J Psychiatr Res
PUBLISHED: 03-26-2013
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Both childhood maltreatment and adult stressful life events are established risk factors for the onset of depression in adulthood. However, the interaction between them can be viewed through two conflicting frameworks. Under a mismatch hypothesis stressful childhoods allow adaptive programming for a stressful adulthood and so can be protective. Only when childhood and adulthood do not match is there a risk of behavioural problems. Alternatively, under the cumulative stress hypothesis we expect increased risk with each additional stressor. It has also been suggested that an individuals genetic background may determine the extent they undergo adaptive programming, and so which of these two hypotheses is relevant. In this study we test for an interaction between exposure to childhood maltreatment and adult stressful life events in a retrospective sample of 455 individuals, using major depression as the outcome. We also test whether this interaction differs by genotype at the 5-HTTLPR, a candidate for an individuals plasticity to adaptive programming. Early maltreatment and stressful life events in adulthood interacted to produce increased risk for depression over each individually (p = 0.055). This supports the cumulative stress hypothesis over the mismatch hypothesis, at least with respect to severe environmental risk factors. This effect was not altered by 5-HTTLPR allele, suggesting there was no difference by genotype in adaptive programming to these events. We suggest that the apparent additional vulnerability to stressful events of those who have experienced maltreatment has clinical relevance, highlighting the importance of providing support beyond the immediate aftermath of maltreatment into adulthood.
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Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: genome-wide association study of both common and rare variants.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 03-17-2013
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Attention-deficit hyperactivity disorder (ADHD) is a complex polygenic disorder. This study aimed to discover common and rare DNA variants associated with ADHD in a large homogeneous Han Chinese ADHD case-control sample. The sample comprised 1,040 cases and 963 controls. All cases met DSM-IV ADHD diagnostic criteria. We used the Affymetrix6.0 array to assay both single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Genome-wide association analyses were performed using PLINK. SNP-heritability and SNP-genetic correlations with ADHD in Caucasians were estimated with genome-wide complex trait analysis (GCTA). Pathway analyses were performed using the Interval enRICHment Test (INRICH), the Disease Association Protein-Protein Link Evaluator (DAPPLE), and the Genomic Regions Enrichment of Annotations Tool (GREAT). We did not find genome-wide significance for single SNPs but did find an increased burden of large, rare CNVs in the ADHD sample (P = 0.038). SNP-heritability was estimated to be 0.42 (standard error, 0.13, P = 0.0017) and the SNP-genetic correlation with European Ancestry ADHD samples was 0.39 (SE 0.15, P = 0.0072). The INRICH, DAPPLE, and GREAT analyses implicated several gene ontology cellular components, including neuron projections and synaptic components, which are consistent with a neurodevelopmental pathophysiology for ADHD. This study suggested the genetic architecture of ADHD comprises both common and rare variants. Some common causal variants are likely to be shared between Han Chinese and Caucasians. Complex neurodevelopmental networks may underlie ADHDs etiology.
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Catatonia in DSM-5.
Schizophr. Res.
PUBLISHED: 03-15-2013
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Although catatonia has historically been associated with schizophrenia and is listed as a subtype of the disorder, it can occur in patients with a primary mood disorder and in association with neurological diseases and other general medical conditions. Consequently, catatonia secondary to a general medical condition was included as a new condition and catatonia was added as an episode specifier of major mood disorders in DSM-IV. Different sets of criteria are utilized to diagnose catatonia in schizophrenia and primary mood disorders versus neurological/medical conditions in DSM-IV, however, and catatonia is a codable subtype of schizophrenia but a specifier for major mood disorders without coding. In part because of this discrepant treatment across the DSM-IV manual, catatonia is frequently not recognized by clinicians. Additionally, catatonia is known to occur in several conditions other than schizophrenia, major mood disorders, or secondary to a general medical condition. Four changes are therefore made in the treatment of catatonia in DSM-5. A single set of criteria will be utilized to diagnose catatonia across the diagnostic manual and catatonia will be a specifier for both schizophrenia and major mood disorders. Additionally, catatonia will also be a specifier for other psychotic disorders, including schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, and substance-induced psychotic disorder. A new residual category of catatonia not otherwise specified will be added to allow for the rapid diagnosis and specific treatment of catatonia in severely ill patients for whom the underlying diagnosis is not immediately available. These changes should improve the consistent recognition of catatonia across the range of psychiatric disorders and facilitate its specific treatment.
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Attenuated psychosis syndrome in DSM-5.
Schizophr. Res.
PUBLISHED: 03-01-2013
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Despite advances in the treatment of schizophrenia over the past half-century, the illness is frequently associated with a poor outcome. This is principally related to the late identification and intervention in the course of the illness by which time patients have experienced a substantial amount of socio-occupational decline that can be difficult to reverse. The emphasis has therefore shifted to defining psychosis-risk syndromes and evaluating treatments that can prevent transition to psychosis in these ultra-high risk groups. To consider the appropriateness of adding psychosis risk syndrome to our diagnostic nomenclature, the psychotic disorders work group extensively reviewed all available data, consulted a range of experts, and carefully considered the variety of expert and public comments on the topic. It was clear that reliable methods were available to define a syndrome characterized by sub-threshold psychotic symptoms (in severity or duration) and which was associated with a very significant increase in the risk of development of a full-fledged psychotic disorder (schizophrenia spectrum, psychotic mood disorder, and other psychotic disorders) within the next year. At the same time, the majority of individuals with "attenuated psychotic symptoms" had one or more other current psychiatric comorbid conditions (usually mood or anxiety disorders, substance use disorder; Fusar-Poli 2012) and exhibited a range of psychiatric outcomes other than conversion to psychosis (significant proportions either fully recover or develop some other psychiatric disorder, with a minority developing a psychotic disorder). Although the reliability of the diagnosis is well established in academic and research settings, it was found to be less so in community and other clinical settings. Furthermore, the nosological relationship of attenuated psychosis syndrome (APS) to schizotypal personality disorder and other psychiatric conditions was unclear. Further study will hopefully resolve these questions. The work group decided to recommend the inclusion of attenuated psychosis syndrome as a category in the appendix (Section 3) of DSM-5 as a condition for further study.
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Schizoaffective Disorder in the DSM-5.
Schizophr. Res.
PUBLISHED: 02-28-2013
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Characterization of patients with both psychotic and mood symptoms, either concurrently or at different points during their illness, has always posed a nosological challenge and this is reflected in the poor reliability, low diagnostic stability, and questionable validity of DSM-IV Schizoaffective Disorder. The clinical reality of the frequent co-occurrence of psychosis and Mood Episodes has also resulted in over-utilization of a diagnostic category that was originally intended to only rarely be needed. In the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, an effort is made to improve reliability of this condition by providing more specific criteria and the concept of Schizoaffective Disorder shifts from an episode diagnosis in DSM-IV to a life-course of the illness in DSM-5. When psychotic symptoms occur exclusively during a Mood Episode, DSM-5 indicates that the diagnosis is the appropriate Mood Disorder with Psychotic Features, but when such a psychotic condition includes at least a two-week period of psychosis without prominent mood symptoms, the diagnosis may be either Schizoaffective Disorder or Schizophrenia. In the DSM-5, the diagnosis of Schizoaffective Disorder can be made only if full Mood Disorder episodes have been present for the majority of the total active and residual course of illness, from the onset of psychotic symptoms up until the current diagnosis. In earlier DSM versions the boundary between Schizophrenia and Schizoaffective Disorder was only qualitatively defined, leading to poor reliability. This change will provide a clearer separation between Schizophrenia with mood symptoms from Schizoaffective Disorder and will also likely reduce rates of diagnosis of Schizoaffective Disorder while increasing the stability of this diagnosis once made.
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Logic and justification for dimensional assessment of symptoms and related clinical phenomena in psychosis: relevance to DSM-5.
Schizophr. Res.
PUBLISHED: 02-25-2013
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Work on the causes and treatment of schizophrenia and other psychotic disorders has long recognized the heterogeneity of the symptoms that can be displayed by individuals with these illnesses. Further, researchers have increasingly emphasized the ways in which the severity of different symptoms of this illness can vary across individuals, and have provided evidence that the severity of such symptoms can predict other important aspects of the illness, such as the degree of cognitive and/or neurobiological deficits. Additionally, research has increasingly emphasized that the boundaries between nosological entities may not be categorical and that the comorbidity of disorders may reflect impairments in common dimensions of genetic variation, human behavior and neurobiological function. As such, it is critical to focus on a dimensional approach to the assessment of symptoms and clinically relevant phenomena in psychosis, so as to increase attention to and understanding of the causes and consequences of such variation. In the current article, we review the logic and justification for including dimensional assessment of clinical symptoms in the evaluation of psychosis in the Fifth Edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-5).
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Structure of the psychotic disorders classification in DSM-5.
Schizophr. Res.
PUBLISHED: 02-23-2013
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Schizophrenia spectrum disorders attract great interest among clinicians, researchers, and the lay public. While the diagnostic features of schizophrenia have remained unchanged for more than 100 years, the mechanism of illness has remained elusive. There is increasing evidence that the categorical diagnosis of schizophrenia and other psychotic disorders contributes to this lack of progress. The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) continues the categorical classification of psychiatric disorders since the research needed to establish a new nosology of equal or greater validity is lacking. However, even within a categorical system, the DSM-5 aims to capture the underlying dimensional structure of psychosis. The domains of psychopathology that define psychotic disorders are presented not simply as features of schizophrenia. The level, the number, and the duration of psychotic signs and symptoms are used to demarcate psychotic disorders from each other. Finally, the categorical assessment is complemented with a dimensional assessment of psychosis that allows for more specific and individualized assessment of patients. The structure of psychosis as outlined in the DSM-5 may serve as a stepping-stone towards a more valid classification system, as we await new data to redefine psychotic disorders.
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The internet is parents main source of information about psychiatric manifestations of 22q11.2 deletion syndrome (22q11.2DS).
Eur J Med Genet
PUBLISHED: 02-11-2013
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With advances in laboratory technology, an increasing number of potentially pathogenic CNVs is recognised. The phenotypic effects of some CNVs are well characterised, however, it remains unclear how much information reaches the parents of affected children and by what route. The 22q11.2 deletion syndrome (del22q11.2) is caused by the deletion of approximately 40 genes from the long arm of chromosome 22 and was first described in 1955 [1]. Our study reports the extent to which parents of an affected child are aware of the various manifestation of the condition and describes how they first learned about these potential problems.
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Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.
, S Hong Lee, Stephan Ripke, Benjamin M Neale, Stephen V Faraone, Shaun M Purcell, Roy H Perlis, Bryan J Mowry, Anita Thapar, Michael E Goddard, John S Witte, Devin Absher, Ingrid Agartz, Huda Akil, Farooq Amin, Ole A Andreassen, Adebayo Anjorin, Richard Anney, Verneri Anttila, Dan E Arking, Philip Asherson, Maria H Azevedo, Lena Backlund, Judith A Badner, Anthony J Bailey, Tobias Banaschewski, Jack D Barchas, Michael R Barnes, Thomas B Barrett, Nicholas Bass, Agatino Battaglia, Michael Bauer, Mònica Bayés, Frank Bellivier, Sarah E Bergen, Wade Berrettini, Catalina Betancur, Thomas Bettecken, Joseph Biederman, Elisabeth B Binder, Donald W Black, Douglas H R Blackwood, Cinnamon S Bloss, Michael Boehnke, Dorret I Boomsma, Gerome Breen, René Breuer, Richard Bruggeman, Paul Cormican, Nancy G Buccola, Jan K Buitelaar, William E Bunney, Joseph D Buxbaum, William F Byerley, Enda M Byrne, Sian Caesar, Wiepke Cahn, Rita M Cantor, Miguel Casas, Aravinda Chakravarti, Kimberly Chambert, Khalid Choudhury, Sven Cichon, C Robert Cloninger, David A Collier, Edwin H Cook, Hilary Coon, Bru Cormand, Aiden Corvin, William H Coryell, David W Craig, Ian W Craig, Jennifer Crosbie, Michael L Cuccaro, David Curtis, Darina Czamara, Susmita Datta, Geraldine Dawson, Richard Day, Eco J De Geus, Franziska Degenhardt, Srdjan Djurovic, Gary J Donohoe, Alysa E Doyle, Jubao Duan, Frank Dudbridge, Eftichia Duketis, Richard P Ebstein, Howard J Edenberg, Josephine Elia, Sean Ennis, Bruno Etain, Ayman Fanous, Anne E Farmer, I Nicol Ferrier, Matthew Flickinger, Eric Fombonne, Tatiana Foroud, Josef Frank, Barbara Franke, Christine Fraser, Robert Freedman, Nelson B Freimer, Christine M Freitag, Marion Friedl, Louise Frisén, Louise Gallagher, Pablo V Gejman, Lyudmila Georgieva, Elliot S Gershon, Daniel H Geschwind, Ina Giegling, Michael Gill, Scott D Gordon, Katherine Gordon-Smith, Elaine K Green, Tiffany A Greenwood, Dorothy E Grice, Magdalena Gross, Detelina Grozeva, Weihua Guan, Hugh Gurling, Lieuwe de Haan, Jonathan L Haines, Hakon Hakonarson, Joachim Hallmayer, Steven P Hamilton, Marian L Hamshere, Thomas F Hansen, Annette M Hartmann, Martin Hautzinger, Andrew C Heath, Anjali K Henders, Stefan Herms, Ian B Hickie, Maria Hipolito, Susanne Hoefels, Peter A Holmans, Florian Holsboer, Witte J Hoogendijk, Jouke-Jan Hottenga, Christina M Hultman, Vanessa Hus, Andrés Ingason, Marcus Ising, Stéphane Jamain, Edward G Jones, Ian Jones, Lisa Jones, Jung-Ying Tzeng, Anna K Kähler, René S Kahn, Radhika Kandaswamy, Matthew C Keller, James L Kennedy, Elaine Kenny, Lindsey Kent, Yunjung Kim, George K Kirov, Sabine M Klauck, Lambertus Klei, James A Knowles, Martin A Kohli, Daniel L Koller, Bettina Konte, Ania Korszun, Lydia Krabbendam, Robert Krasucki, Jonna Kuntsi, Phoenix Kwan, Mikael Landén, Niklas Långström, Mark Lathrop, Jacob Lawrence, William B Lawson, Marion Leboyer, David H Ledbetter, Phil H Lee, Todd Lencz, Klaus-Peter Lesch, Douglas F Levinson, Cathryn M Lewis, Jun Li, Paul Lichtenstein, Jeffrey A Lieberman, Dan-Yu Lin, Don H Linszen, Chunyu Liu, Falk W Lohoff, Sandra K Loo, Catherine Lord, Jennifer K Lowe, Susanne Lucae, Donald J MacIntyre, Pamela A F Madden, Elena Maestrini, Patrik K E Magnusson, Pamela B Mahon, Wolfgang Maier, Anil K Malhotra, Shrikant M Mane, Christa L Martin, Nicholas G Martin, Manuel Mattheisen, Keith Matthews, Morten Mattingsdal, Steven A McCarroll, Kevin A McGhee, James J McGough, Patrick J McGrath, Peter McGuffin, Melvin G McInnis, Andrew McIntosh, Rebecca McKinney, Alan W McLean, Francis J McMahon, William M McMahon, Andrew McQuillin, Helena Medeiros, Sarah E Medland, Sandra Meier, Ingrid Melle, Fan Meng, Jobst Meyer, Christel M Middeldorp, Lefkos Middleton, Vihra Milanova, Ana Miranda, Anthony P Monaco, Grant W Montgomery, Jennifer L Moran, Daniel Moreno-De-Luca, Gunnar Morken, Derek W Morris, Eric M Morrow, Valentina Moskvina, Pierandrea Muglia, Thomas W Mühleisen, Walter J Muir, Bertram Müller-Myhsok, Michael Murtha, Richard M Myers, Inez Myin-Germeys, Michael C Neale, Stan F Nelson, Caroline M Nievergelt, Ivan Nikolov, Vishwajit Nimgaonkar, Willem A Nolen, Markus M Nöthen, John I Nurnberger, Evaristus A Nwulia, Dale R Nyholt, Colm O'Dushlaine, Robert D Oades, Ann Olincy, Guiomar Oliveira, Line Olsen, Roel A Ophoff, Urban Osby, Michael J Owen, Aarno Palotie, Jeremy R Parr, Andrew D Paterson, Carlos N Pato, Michele T Pato, Brenda W Penninx, Michele L Pergadia, Margaret A Pericak-Vance, Benjamin S Pickard, Jonathan Pimm, Joseph Piven, Danielle Posthuma, James B Potash, Fritz Poustka, Peter Propping, Vinay Puri, Digby J Quested, Emma M Quinn, Josep Antoni Ramos-Quiroga, Henrik B Rasmussen, Soumya Raychaudhuri, Karola Rehnström, Andreas Reif, Marta Ribasés, John P Rice, Marcella Rietschel, Kathryn Roeder, Herbert Roeyers, Lizzy Rossin, Aribert Rothenberger, Guy Rouleau, Douglas Ruderfer, Dan Rujescu, Alan R Sanders, Stephan J Sanders, Susan L Santangelo, Joseph A Sergeant, Russell Schachar, Martin Schalling, Alan F Schatzberg, William A Scheftner, Gerard D Schellenberg, Stephen W Scherer, Nicholas J Schork, Thomas G Schulze, Johannes Schumacher, Markus Schwarz, Edward Scolnick, Laura J Scott, Jianxin Shi, Paul D Shilling, Stanley I Shyn, Jeremy M Silverman, Susan L Slager, Susan L Smalley, Johannes H Smit, Erin N Smith, Edmund J S Sonuga-Barke, David St Clair, Matthew State, Michael Steffens, Hans-Christoph Steinhausen, John S Strauss, Jana Strohmaier, T Scott Stroup, James S Sutcliffe, Peter Szatmari, Szabocls Szelinger, Srinivasa Thirumalai, Robert C Thompson, Alexandre A Todorov, Federica Tozzi, Jens Treutlein, Manfred Uhr, Edwin J C G van den Oord, Gerard van Grootheest, Jim van Os, Astrid M Vicente, Veronica J Vieland, John B Vincent, Peter M Visscher, Christopher A Walsh, Thomas H Wassink, Stanley J Watson, Myrna M Weissman, Thomas Werge, Thomas F Wienker, Ellen M Wijsman, Gonneke Willemsen, Nigel Williams, A Jeremy Willsey, Stephanie H Witt, Wei Xu, Allan H Young, Timothy W Yu, Stanley Zammit, Peter P Zandi, Peng Zhang, Frans G Zitman, Sebastian Zöllner, Bernie Devlin, John R Kelsoe, Pamela Sklar, Mark J Daly, Michael C O'Donovan, Nicholas Craddock, Patrick F Sullivan, Jordan W Smoller, Kenneth S Kendler, Naomi R Wray.
Nat. Genet.
PUBLISHED: 02-10-2013
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Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohns disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
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SGCE mutations cause psychiatric disorders: clinical and genetic characterization.
Brain
PUBLISHED: 02-01-2013
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Myoclonus dystonia syndrome is a childhood onset hyperkinetic movement disorder characterized by predominant alcohol responsive upper body myoclonus and dystonia. A proportion of cases are due to mutations in the maternally imprinted SGCE gene. Previous studies have suggested that patients with SGCE mutations may have an increased rate of psychiatric disorders. We established a cohort of patients with myoclonus dystonia syndrome and SGCE mutations to determine the extent to which psychiatric disorders form part of the disease phenotype. In all, 89 patients with clinically suspected myoclonus dystonia syndrome were recruited from the UK and Ireland. SGCE was analysed using direct sequencing and for copy number variants. In those patients where no mutation was found TOR1A (GAG deletion), GCH1, THAP1 and NKX2-1 were also sequenced. SGCE mutation positive cases were systematically assessed using standardized psychiatric interviews and questionnaires and compared with a disability-matched control group of patients with alcohol responsive tremor. Nineteen (21%) probands had a SGCE mutation, five of which were novel. Recruitment of family members increased the affected SGCE mutation positive group to 27 of whom 21 (77%) had psychiatric symptoms. Obsessive-compulsive disorder was eight times more likely (P < 0.001) in mutation positive cases, compulsivity being the predominant feature (P < 0.001). Generalized anxiety disorder (P = 0.003) and alcohol dependence (P = 0.02) were five times more likely in mutation positive cases than tremor controls. SGCE mutations are associated with a specific psychiatric phenotype consisting of compulsivity, anxiety and alcoholism in addition to the characteristic motor phenotype. SGCE mutations are likely to have a pleiotropic effect in causing both motor and specific psychiatric symptoms.
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Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes.
Am. J. Hum. Genet.
PUBLISHED: 01-31-2013
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Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6-1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.
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Variation in tau isoform expression in different brain regions and disease states.
Neurobiol. Aging
PUBLISHED: 01-17-2013
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Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian disorder. Abnormal tau inclusions, in selected regions of the brain, are a hallmark of the disease and the H1 haplotype of MAPT, the gene encoding tau, is the major risk factor in PSP. A 3-repeat and 4-repeat (4R) tau isoform ratio imbalance has been strongly implicated as a cause of disease. Thus, understanding tau isoform regional expression in disease and pathology-free states is crucial to elucidating the mechanisms involved in PSP and other tauopathies. We used a tau isoform-specific fluorescent assay to investigate relative 4R-tau expression in 6 different brain regions in PSP cases and healthy control samples. We identified a marked difference in 4R-tau relative expression, across brain regions and between MAPT haplotypes. Highest 4R-tau expression levels were identified in the globus pallidus compared with pons, cerebellum, and frontal cortex. 4R-tau expression levels were related to the MAPT H1 and H1c haplotypes. Similar regional variation was seen in PSP case and in control samples.
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Schizophrenia two-hit hypothesis in velo-cardio facial syndrome.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 01-17-2013
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Deletion of chr22q11 gives rise to velo-cardio facial syndrome (VCFS) and increases schizophrenia risk. The source of this elevated risk although unknown could result from stochastic, environmental, or genetic factors, the latter encompassing a range of complexity from polygenic mechanisms to "second-hit" mutations. For this study we tested the two-hit hypothesis where additional risk is conferred through a second CNV. We identified large (>100 kb) CNVs in 48 VCFS cases (23 with psychosis--25 without) and show in the psychotic VCFS group there is a significant (P = 0.02) increase in the average size of CNVs (354-227 kb). To identify second-hit loci we focused on individuals possessing gene-centric CNVs and through literature mining identified 4 (31%) psychotic VCFS individuals (n = 13) that overlapped loci previously implicated in neuropsychiatric disorders compared to 1 (10%) from the non-psychotic VCFS individuals (n = 10). For replication 17 VCFS patients with schizophrenia from the molecular genetics of schizophrenia dataset were used to identify further CNVs. Thirteen individuals possessing gene-centric CNVs were identified including 3 (23%) individuals possessing a potential second-hit, taking the overall total in the psychotic VCFS group (n = 26) to 7 (27%) potential second-hit loci. Notably a deletion in a psychotic VCFS patient at 2q23.1 hit the gene MBD5 which when deleted gives rise to intellectual disability, epilepsy, and autistic features. Through this study we potentially extend this phenotypic spectrum to include schizophrenia. Our results suggest the two-hit hypothesis may be relevant to a proportion of VCFS patients with psychosis but sample sizes are small and further studies warranted.
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Mosaic copy number variation in schizophrenia.
Eur. J. Hum. Genet.
PUBLISHED: 01-16-2013
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Recent reports suggest that somatic structural changes occur in the human genome, but how these genomic alterations might contribute to disease is unknown. Using samples collected as part of the International Schizophrenia Consortium (schizophrenia, n=3518; control, n=4238) recruited across multiple university research centers, we assessed single-nucleotide polymorphism genotyping arrays for evidence of chromosomal anomalies. Data from genotyping arrays on each individual were processed using Birdsuite and analyzed with PLINK. We validated potential chromosomal anomalies using custom nanostring probes and quantitative PCR. We estimate chromosomal alterations in the schizophrenia population to be 0.42%, which is not significantly different from controls (0.26%). We identified and validated a set of four extremely large (>10?Mb) chromosomal anomalies in subjects with schizophrenia, including a chromosome 8 trisomy and deletion of the q arm of chromosome 7. These data demonstrate that chromosomal anomalies are present at low frequency in blood cells of both control and schizophrenia subjects.
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Specific parental depression symptoms as risk markers for new-onset depression in high-risk offspring.
J Clin Psychiatry
PUBLISHED: 01-10-2013
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To disaggregate the depression construct and investigate whether specific depression symptoms in parents with a history of recurrent depression are clinical risk markers for future depression in their high-risk offspring. Our hypothesis was that parental symptoms of the type that might impact offspring would most likely be of greatest importance.
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Clinical and cognitive characteristics of children with attention-deficit hyperactivity disorder, with and without copy number variants.
Br J Psychiatry
PUBLISHED: 11-03-2011
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Submicroscopic, rare chromosomal copy number variants (CNVs) contribute to neurodevelopmental disorders but it is not known whether they define atypical clinical cases.
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Evaluation of medication list completeness, safety, and annotations.
AMIA Annu Symp Proc
PUBLISHED: 10-22-2011
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Clinical documents frequently contain a list of a patients medications. Missing information about the dosage, route, or frequency of a medication impairs clinical communication and may harm patients. We examined 253 medication lists. There were 181 lists (72%) with at least one medication missing a dose, route, or frequency. Missing information was judged to be potentially harmful in 47 of the lists (19% of 253) by three physician reviewers (kappa=0.69). We also observed that many lists contained additional information included as annotations, prompting a secondary thematic analysis of the annotations. Fifty-five of the 253 lists (22%) contained one or more annotations. The most frequent types of annotations were comments about the patients medical history, the clinicians treatment plan changes, and the patients adherence to a medication. Future development of electronic medication reconciliation tools to improve medication list completeness should also support annotating the medication list in a flexible manner.
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Cannabis, COMT and psychotic experiences.
Br J Psychiatry
PUBLISHED: 09-22-2011
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A putative interaction between cannabis and variation at rs4680 within the catechol-methyl-transferase (COMT) gene on psychosis has been reported, but not adequately replicated.
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Phenotype evaluation and genomewide linkage study of clinical variables in schizophrenia.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 09-14-2011
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Genetic factors are likely to influence clinical variation in schizophrenia, but it is unclear which variables are most suitable as phenotypes and which molecular genetic loci are involved. We evaluated clinical variable phenotypes and applied suitable phenotypes in genome-wide covariate linkage analysis. We ascertained 170 affected relative pairs (168 sibling-pairs and two avuncular pairs) with DSM-IV schizophrenia or schizoaffective disorder from the United Kingdom. We defined psychotic symptom dimensions, age at onset (AAO), and illness course using the OPCRIT checklist. We evaluated phenotypes using within sibling-pair correlations and applied suitable phenotypes in multipoint covariate linkage analysis based on 372 microsatellite markers at ?10 cM intervals. The statistical significance of linkage results was assessed by simulation. The positive and disorganized symptom dimensions, AAO, and illness course qualified as suitable phenotypes. There were no genome-wide significant linkage results. There was suggestive evidence of linkage for the positive dimension on chromosomes 2q32, 10q26, and 20q12; the disorganized dimension on 8p21 and 17q21; and illness course on 2q33 and 22q11. The linkage peak for disorganization on 17q21 remained suggestive after correction for multiple testing. To our knowledge, this is the first study to integrate phenotype evaluation and genome-wide covariate linkage analysis for symptom dimensions and illness history variables in sibling-pairs with schizophrenia. The significant within-pair correlations strengthen the evidence that some clinical variables within schizophrenia are suitable phenotypes for molecular genetic investigations. At present there are no genome-wide significant linkage results for these phenotypes, but a number of suggestive findings warrant further investigation.
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Quantum chemical analysis of the unfolding of a penta-glycyl 3(10)-helix initiated by HO(?), HO2(?), and O2(-?).
J Chem Phys
PUBLISHED: 07-27-2011
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In this study, the thermodynamic functions of hydrogen abstraction from the C(?) and amide nitrogen of Gly(3) in a homo-pentapeptide (N-Ac-GGGGG-NH(2); G5) by HO(?), HO(2)(?), and O(2)(-?) were computed using the Becke three-parameter Lee-Yang-Parr (B3LYP) density functional. The thermodynamic functions, standard enthalpy (?H°), Gibbs free energy (?G°), and entropy (?S°), of these reactions were computed with G5 in the 3(10)-helical (G5(Hel)) and fully-extended (G5(Ext)) conformations at the B3LYP/6-31G(d) and B3LYP/6-311+G(d,p) levels of theory, both in the gas phase and using the conductor-like polarizable continuum model implicit water model. H abstraction is more favorable at the C(?) than at the amide nitrogen. The secondary structure of G5 affects the bond dissociation energy of the H-C(?), but has a negligible effect on the dissociation energy of the H-N bond. The HO(?) radical is the strongest hydrogen abstractor, followed by HO(2)(?), and finally O(2)(-?). The secondary structure elements, such as H-bonds in the 3(10)-helix, protect the peptide from radical attack by disabling the potential electron delocalization at the C(?), which is possible when G5 is in the extended conformation. The unfolding of the peptide radicals is more favorable than the unfolding of G5(Hel); however, only the HO(?) can initiate the unfolding of G5(Hel) and the formation of G5(Ext)(?). These results are relevant to peptides that are prone to undergoing transitions from helical structures to ?-sheets in the cellular condition known as "oxidative stress" and the results are discussed in this context.
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Common variants at VRK2 and TCF4 conferring risk of schizophrenia.
Hum. Mol. Genet.
PUBLISHED: 07-26-2011
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Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)).
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Independent estimation of the frequency of rare CNVs in the UK population confirms their role in schizophrenia.
Schizophr. Res.
PUBLISHED: 07-05-2011
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Several large, rare chromosomal copy number variants (CNVs) have recently been shown to increase risk for schizophrenia and other neuropsychiatric disorders including autism, ADHD, learning difficulties and epilepsy.
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De novo rates and selection of schizophrenia-associated copy number variants.
Biol. Psychiatry
PUBLISHED: 06-01-2011
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At least 10 large and rare recurrent DNA copy number variants (CNVs) have been identified as risk factors for schizophrenia and other neurodevelopmental disorders. Because such conditions are associated with reduced fecundity, these pathogenic CNVs should be filtered out from the population by selection and must be replenished by de novo events.
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Quantum chemical analysis of the unfolding of a penta-alanyl 3(10)-helix initiated by HO(•), HO2(•) and O2(-•).
J Phys Chem B
PUBLISHED: 06-01-2011
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In order to elucidate the mechanisms of radical-initiated unfolding of a helix, the thermodynamic functions of hydrogen abstraction from the C(?), C(?), and amide nitrogen of Ala(3) in a homopeptapeptide (N-Ac-AAAAA-NH(2); A5) by HO(•), HO(2)(•), and O(2)(-•) were computed using the B3LYP density functional. The thermodynamic functions, standard enthalpy (?H(o)), Gibbs free energy (?G(o)), and entropy (?S(o)), of the reactants and products of these reactions were computed with A5 in the 3(10)-helical (A5(Hel)) and fully extended (A5(Ext)) conformations at the B3LYP/6-31G(d) and B3LYP/6-311+G(d,p) levels of theory, both in the gas phase and using the C-PCM implicit water model. With quantum chemical calculations, we have shown that H abstraction is the most favorable at the C(?), followed by the C(?), then amide N in a model helix. The secondary structure has a strong influence on the bond dissociation energy of the H-C(?), but a negligible effect on the dissociation energy of the H-CH(2) and H-N bonds. The HO(•) radical is the strongest hydrogen abstractor, followed by HO(2)(•) and finally O(2)(-•). More importantly, secondary structure elements, such as H-bonds in the 3(10)-helix, protect the peptide from radical attack by hindering the potential electron delocalization at the C(?) when the peptide is in the extended conformation. We also show that he unfolding of the A5 peptide radicals have a significantly higher propensity to unfold than the closed shell A5 peptide and confirm that only the HO(•) can initiate the unfolding of A5(Hel) and the formation of A5(Ext)(•). By comparing the structures, energies, and thermodynamic functions of A5 and its radical derivatives, we have shown how free radicals can initiate the unfolding of helical structures to ?-sheets in the cellular condition known as oxidative stress.
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Association between TCF4 and schizophrenia does not exert its effect by common nonsynonymous variation or by influencing cis-acting regulation of mRNA expression in adult human brain.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 03-21-2011
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Large collaborative Genome-wide Association studies of schizophrenia have identified genes and genomic regions that are associated with the disorder at highly stringent levels of statistical significance. Among these, transcription factor 4 (TCF4) is one of the best supported although the associated SNP (rs9960767) is located within intron 3 and has no obvious function. Seeking the mechanism at TCF responsible for the association, we examined TCF4 for coding variants, and for cis regulated variation in TCF4 gene expression correlated with the associated SNP using an assay to detect differential allelic expression. Using data from the 1000 genomes project, we were unable to identify any nonsynonymous coding variants at the locus. Allele specific expression analysis using human post mortem brain samples revealed no evidence for cis-regulated mRNA expression related to genotype at the schizophrenia associated SNP. We conclude that association between schizophrenia and TCF4 is not mediated by a relatively common non-synonymous variant, or by a variant that alters mRNA expression as measured in adult human brain. It remains possible that the risk allele at this locus exerts effects on expression exclusively in a developmental context, in cell types or brain regions not adequately represented in our analysis, or through post-transcriptional effects, for example in the abundance of the protein or its sub-cellular distribution.
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Analysis of neurogranin (NRGN) in schizophrenia.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 03-11-2011
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A recent study reported a genome-wide significant association between schizophrenia and rs12807809-a SNP located approximately 3 kbp upstream of the neurogranin gene (NRGN). We sought to determine if (a) NRGN contains common exonic variants or variants affecting expression (eQTLs) that could account for the association with rs12807809 and (b) there exist rare non-synonymous highly penetrant variants that could potentially confer high risk of schizophrenia. We sequenced all four exons of NRGN in a screening set of 14 individuals but found no novel common polymorphisms. We additionally sequenced the coding exons in up to 1,113 individuals (699 cases) but this revealed only a singleton-coding variant in exon 2 (G246T leading to Gly-55 ? Val amino acid change) in which prediction of function analysis suggested is likely to be benign. Finally, analysis of a brain expression dataset of at least 130 individuals did not identify any eQTLs that were correlated with associated SNP rs12807809 following correction for multiple testing.
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Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimers disease.
Paul Hollingworth, Denise Harold, Rebecca Sims, Amy Gerrish, Jean-Charles Lambert, Minerva M Carrasquillo, Richard Abraham, Marian L Hamshere, Jaspreet Singh Pahwa, Valentina Moskvina, Kimberley Dowzell, Nicola Jones, Alexandra Stretton, Charlene Thomas, Alex Richards, Dobril Ivanov, Caroline Widdowson, Jade Chapman, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K Lupton, Carol Brayne, David C Rubinsztein, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Kristelle S Brown, Peter A Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Clive Holmes, David Mann, A David Smith, Helen Beaumont, Donald Warden, Gordon Wilcock, Seth Love, Patrick G Kehoe, Nigel M Hooper, Emma R L C Vardy, John Hardy, Simon Mead, Nick C Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Eckart Rüther, Britta Schürmann, Reiner Heun, Heike Kölsch, Hendrik van den Bussche, Isabella Heuser, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, John Gallacher, Michael Hüll, Dan Rujescu, Ina Giegling, Alison M Goate, John S K Kauwe, Carlos Cruchaga, Petra Nowotny, John C Morris, Kevin Mayo, Kristel Sleegers, Karolien Bettens, Sebastiaan Engelborghs, Peter P De Deyn, Christine Van Broeckhoven, Gill Livingston, Nicholas J Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis Deloukas, Ammar Al-Chalabi, Christopher E Shaw, Magda Tsolaki, Andrew B Singleton, Rita Guerreiro, Thomas W Mühleisen, Markus M Nöthen, Susanne Moebus, Karl-Heinz Jöckel, Norman Klopp, H-Erich Wichmann, V Shane Pankratz, Sigrid B Sando, Jan O Aasly, Maria Barcikowska, Zbigniew K Wszolek, Dennis W Dickson, Neill R Graff-Radford, Ronald C Petersen, , Cornelia M van Duijn, Monique M B Breteler, M Arfan Ikram, Anita L Destefano, Annette L Fitzpatrick, Oscar Lopez, Lenore J Launer, Sudha Seshadri, Claudine Berr, Dominique Campion, Jacques Epelbaum, Jean-Francois Dartigues, Christophe Tzourio, Annick Alpérovitch, Mark Lathrop, Thomas M Feulner, Patricia Friedrich, Caterina Riehle, Michael Krawczak, Stefan Schreiber, Manuel Mayhaus, S Nicolhaus, Stefan Wagenpfeil, Stacy Steinberg, Hreinn Stefansson, Kari Stefansson, Jón Snaedal, Sigurbjorn Bjornsson, Palmi V Jonsson, Vincent Chouraki, Benjamin Genier-Boley, Mikko Hiltunen, Hilkka Soininen, Onofre Combarros, Diana Zelenika, Marc Delepine, María J Bullido, Florence Pasquier, Ignacio Mateo, Ana Frank-García, Elisa Porcellini, Olivier Hanon, Eliecer Coto, Victoria Alvarez, Paolo Bosco, Gabriele Siciliano, Michelangelo Mancuso, Francesco Panza, Vincenzo Solfrizzi, Benedetta Nacmias, Sandro Sorbi, Paola Bossù, Paola Piccardi, Beatrice Arosio, Giorgio Annoni, Davide Seripa, Alberto Pilotto, Elio Scarpini, Daniela Galimberti, Alexis Brice, Didier Hannequin, Federico Licastro, Lesley Jones, Peter A Holmans, Thorlakur Jonsson, Matthias Riemenschneider, Kevin Morgan, Steven G Younkin, Michael J Owen, Michael O'Donovan, Philippe Amouyel, Julie Williams.
Nat. Genet.
PUBLISHED: 03-10-2011
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We sought to identify new susceptibility loci for Alzheimers disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimers Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ? 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimers disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).
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Neurodevelopmental hypothesis of schizophrenia.
Br J Psychiatry
PUBLISHED: 03-02-2011
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The neurodevelopmental hypothesis of schizophrenia provided a valuable framework that allowed a condition that usually presents with frank disorder in adolescence or early adulthood to be understood at least in part as a consequence of events occurring early in development. However, the implications of the neurodevelopmental hypothesis for nosological conceptions of the disorder can only now be fully appreciated. Recent research indicates genetic overlap between schizophrenia and syndromes in which psychopathology is manifest in childhood and that are often grouped together as neurodevelopmental disorders such as autism-spectrum disorders, intellectual disability and attention-deficit hyperactivity disorder. These findings challenge the aetiological basis of current diagnostic categories and, together with evidence for frequent comorbidity, suggest that we should view the functional psychoses as members of a group of related and overlapping syndromes that result in part from a combination of genetic and environmental effects on brain development and that are associated with specific and general impairments of cognitive function. This has important implications for future research and for the configuration of psychiatric services.
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