Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples

Grey and white matter correlates of recent and remote autobiographical memory retrieval:Insights from the dementias

The capacity to remember self-referential past events relies on the integrity of a distributed neural network. Controversy exists, however, regarding the involvement of specific brain structures for the retrieval of recently experienced versus more distant events. Here, we explored how characteristic patterns of atrophy in neurodegenerative disorders differentially disrupt remote versus recent autobiographical memory. Eleven behavioural-variant frontotemporal dementia, 10 semantic dementia, 15 Alzheimer's disease patients and 14 healthy older Controls completed the Autobiographical Interview. All patient groups displayed significant remote memory impairments relative to Controls. Similarly, recent period retrieval was significantly compromised in behavioural-variant frontotemporal dementia and Alzheimer's disease, yet semantic dementia patients scored in line with Controls. Voxel-based morphometry and diffusion tensor imaging analyses, for all participants combined, were conducted to investigate grey and white matter correlates of remote and recent autobiographical memory retrieval. Neural correlates common to both recent and remote time periods were identified, including the hippocampus, medial prefrontal, and frontopolar cortices, and the forceps minor and left hippocampal portion of the cingulum bundle. Regions exclusively implicated in each time period were also identified. The integrity of the anterior temporal cortices was related to the retrieval of remote memories, whereas the posterior cingulate cortex emerged as a structure significantly associated with recent autobiographical memory retrieval. This study represents the first investigation of the grey and white matter correlates of remote and recent autobiographical memory retrieval in neurodegenerative disorders. Our findings demonstrate the importance of core brain structures, including the medial prefrontal cortex and hippocampus, irrespective of time period, and point towards the contribution of discrete regions in mediating successful retrieval of distant versus recently experienced events

Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed

Sensitivity to interaural timing differences within the envelopes of acoustic waveforms

Interaural-timing-differences (ITDs) are a cue for sound-source localisation and can be conveyed in the temporal-fine-structure (TFS) of low-frequency tones or in the envelope of high-frequency, amplitude-modulated sounds such as sinusoidally amplitude-modulated (SAM) and transposed-tones. Sensitivity to these cues has been measured in human psychophysical experiments and has revealed that the tranposed-tone elicits just-noticeable-differences (JNDs) in ITDs that are equivalent to those of low-frequency pure-tones when the modulation frequency is below 512-Hz. At modulation frequencies above 512-Hz performance rapidly declines for the transposed-tone while sensitivity to ITDs in pure-tones is robust until around 1200-Hz. Furthermore, transposed-tones elicit JNDs smaller than SAM tones. In the present study, ITD JNDs are assessed psychophysically for pure-tones and transposed-tones using off-midline reference locations. The results demonstrate that frequency, whether the ITD is conveyed in the TFS or the envelope, and location, all have a significant effect on human ITD JNDs and suggest that a difference exists in how ITDs are coded neuronally when conveyed by either high- or low-frequency sounds. ITD-sensitive neurons located within several brainstem nuclei display a high degree of phase-locking to both the TFS of low-frequency pure-tones and the envelopes of SAM and transposed-tones. Echoing the psychophysical findings, phase-locking to the waveform envelope at low modulation frequencies is equivalent to that of low-frequency pure-tones, while declining at high rates of modulation to a lesser degree for tranposed-tones than SAM tones. In order to assess factors critical to the localisation of high-frequency sounds a series of electrophysiology experiments were conducted. Recordings were made from single neurons within the inferior colliculus of the guinea pig in response to ITDs conveyed by 18 unique envelope shapes to evaluate how the envelope segments; Pause, Attack, Sustain and Decay each effect ITD JNDs. Amplitude-modulations with envelope shapes comprising relatively long Pause but short Attack durations have been found to elicit the greatest ITD discrimination of high-frequency sounds

The influence of the accessory genome on bacterial pathogen evolution

Bacterial pathogens exhibit significant variation in their genomic content of virulence factors. This reflects the abundance of strategies pathogens evolved to infect host organisms by suppressing host immunity. Molecular arms-races have been a strong driving force for the evolution of pathogenicity, with pathogens often encoding overlapping or redundant functions, such as type III protein secretion effectors and hosts encoding ever more sophisticated immune systems. The pathogens’ frequent exposure to other microbes, either in their host or in the environment, provides opportunities for the acquisition or interchange of mobile genetic elements. These DNA elements accessorise the core genome and can play major roles in shaping genome structure and altering the complement of virulence factors. Here, we review the different mobile genetic elements focusing on the more recent discoveries and highlighting their role in shaping bacterial pathogen evolution

Fostering implementation of health services research findings into practice: a consolidated framework for advancing implementation science

Abstract Background Many interventions found to be effective in health services research studies fail to translate into meaningful patient care outcomes across multiple contexts. Health services researchers recognize the need to evaluate not only summative outcomes but also formative outcomes to assess the extent to which implementation is effective in a specific setting, prolongs sustainability, and promotes dissemination into other settings. Many implementation theories have been published to help promote effective implementation. However, they overlap considerably in the constructs included in individual theories, and a comparison of theories reveals that each is missing important constructs included in other theories. In addition, terminology and definitions are not consistent across theories. We describe the Consolidated Framework For Implementation Research (CFIR) that offers an overarching typology to promote implementation theory development and verification about what works where and why across multiple contexts. Methods We used a snowball sampling approach to identify published theories that were evaluated to identify constructs based on strength of conceptual or empirical support for influence on implementation, consistency in definitions, alignment with our own findings, and potential for measurement. We combined constructs across published theories that had different labels but were redundant or overlapping in definition, and we parsed apart constructs that conflated underlying concepts. Results The CFIR is composed of five major domains: intervention characteristics, outer setting, inner setting, characteristics of the individuals involved, and the process of implementation. Eight constructs were identified related to the intervention (e.g., evidence strength and quality), four constructs were identified related to outer setting (e.g., patient needs and resources), 12 constructs were identified related to inner setting (e.g., culture, leadership engagement), five constructs were identified related to individual characteristics, and eight constructs were identified related to process (e.g., plan, evaluate, and reflect). We present explicit definitions for each construct. Conclusion The CFIR provides a pragmatic structure for approaching complex, interacting, multi-level, and transient states of constructs in the real world by embracing, consolidating, and unifying key constructs from published implementation theories. It can be used to guide formative evaluations and build the implementation knowledge base across multiple studies and settings.http://deepblue.lib.umich.edu/bitstream/2027.42/78272/1/1748-5908-4-50.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/2/1748-5908-4-50-S1.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/3/1748-5908-4-50-S3.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/4/1748-5908-4-50-S4.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/5/1748-5908-4-50.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/6/1748-5908-4-50-S2.PDFPeer Reviewe

What is going on around here? Intolerance of uncertainty predicts threat generalization

Attending to stimuli that share perceptual similarity to learned threats is an adaptive strategy. However, prolonged threat generalization to cues signalling safety is considered a core feature of pathological anxiety. One potential factor that may sustain over-generalization is sensitivity to future threat uncertainty. To assess the extent to which Intolerance of Uncertainty (IU) predicts threat generalization, we recorded skin conductance in 54 healthy participants during an associative learning paradigm, where threat and safety cues varied in perceptual similarity. Lower IU was associated with stronger discrimination between threat and safety cues during acquisition and extinction. Higher IU, however, was associated with generalized responding to threat and safety cues during acquisition, and delayed discrimination between threat and safety cues during extinction. These results were specific to IU, over and above other measures of anxious disposition. These findings highlight: (1) a critical role of uncertainty-based mechanisms in threat generalization, and (2) IU as a potential risk factor for anxiety disorder development

Ganho de peso, dislipidemia e parâmetros alterados para síndrome metabólica em pacientes de primeiro episódio psicótico após seguimento de seis meses

OBJECTIVES: Obesity and metabolic abnormalities are frequent in psychotic patients, including first-episode psychosis. We evaluated weight and metabolic parameters in first-episode psychotic outpatients from the First Episode Psychosis Program, Universidade Federal de São Paulo (UNIFESP). METHOD: Weight, height, waist and hip circumferences, glucose and lipid levels were measured at baseline and after a six-month period. RESULTS: Fifty-seven patients were included and 44 (77.2%) of them finished the study. Patients had a median age of 26.3 years, 60% were men and 43% had a diagnosis of schizophrenia at the endpoint. Weight and BMI values increased significantly during the follow-up (p < 0.01). The average weight gain at the follow-up was 10.1% of the baseline weight (SD = 11.9). Only women presented significant waist abnormalities: at the first assessment the waist mean was 79.12 cm (SD = 10.68) and 6 months later it had increased to 89.65 cm (SD = 11.19, z = -3.182, p = 0.001). After 6 months, the total cholesterol (p = 0.004), and triglyceride levels (p = 0.016) increased, while HDL-cholesterol levels decreased (p = 0.025). During the follow-up period one patient (2.3%) developed diabetes mellitus, one (2.3%) presented altered fasting glucose, 12 (27.2%) patients developed at least two altered parameters for metabolic syndrome and 3 (6.8%) patients developed metabolic syndrome (p = 0.001). DISCUSSION: The results of this study showed that in a short period of time individuals under antipsychotic treatment had their weight increased significantly and developed important metabolic abnormalities. CONCLUSIONS: Clinicians should be aware of these risks, choose an antipsychotic that causes less weight gain and should monitor these patients carefully, and recommend prophylactic measures as diet restriction and physical activities.OBJETIVOS: Obesidade e alterações metabólicas são freqüentes em pacientes psicóticos, inclusive no primeiro episódio psicótico. Foram avaliados peso e parâmetros metabólicos em pacientes em tratamento no Programa de Episódio Psicótico da Universidade Federal de São Paulo (UNIFESP). MÉTODO: Peso, altura, medida de cintura e quadril, glicemia e perfil lipídico foram avaliados no início do tratamento e após seis meses. RESULTADOS: Cinqüenta e sete pacientes foram incluídos no estudo e 44 (72%) concluíram o estudo. Os pacientes apresentavam em média 26,3 anos, 60% eram do sexo masculino e, ao final do estudo, 43% apresentavam diagnóstico de esquizofrenia. Houve aumento significativo do peso e índice de massa corporal durante o estudo (p < 0,01). Em média, o peso aumentou 10,1% do peso inicial (SD = 11,9). Apenas mulheres apresentaram alterações na medida da cintura: no início, a média da cintura era de 79,12 cm (SD = 10,68) e, após seis meses, houve um aumento para 89,65 cm (SD = 11,19, z = -3,182, p = 0,001). Após seis meses, houve aumento do colesterol total (p = 0,004) e triglicérides (p = 0,016), e diminuição dos níveis de colesterol HDL (p = 0,025). No período, um paciente (2,3%) desenvolveu diabetes mellitus, um paciente (2,3%) apresentou glicemia de jejum alterada, 12 (27,2%) desenvolveram pelo menos dois parâmetros alterados para síndrome metabólica, e 3 (6,8%) apresentaram síndrome metabólica (p = 0,001). DISCUSSÃO: Os resultados deste estudo mostram que em um curto período de tempo pacientes em tratamento com antipsicóticos aumentaram substancialmente o peso e desenvolveram importantes alterações metabólicas. CONCLUSÃO: Os clínicos devem estar atentos a esses riscos, escolher medicações que causem menor ganho de peso, devendo monitorar esses pacientes cuidadosamente e recomendar medidas profiláticas como restrição dietética e atividade física.Universidade Federal de São Paulo (UNIFESP) Department of Psychiatry First-episode Psychosis ProgramUNIFESP, Department of Psychiatry First-episode Psychosis ProgramSciEL

A Polymorphism in a Gene Encoding Perilipin 4 Is Associated with Height but not with Bone Measures in Individuals from the Framingham Osteoporosis Study

There is increasing interest in identifying new pathways and candidate genes that confer susceptibility to osteoporosis. There is evidence that adipogenesis and osteogenesis may be related, including a common bone marrow progenitor cell for both adipocytes and osteoblasts. Perilipin 1 (PLIN1) and Perilipin 4 (PLIN4) are members of the PATS family of genes and are involved in lipolysis of intracellular lipid deposits. A previous study reported gender-specific associations between one polymorphism of PLIN1 and bone mineral density (BMD) in a Japanese population. We hypothesized that polymorphisms in PLIN1 and PLIN4 would be associated with bone measures in adult Caucasian participants of the Framingham Osteoporosis Study (FOS). We genotyped 1,206 male and 1,445 female participants of the FOS for four single-nucleotide polymorphism (SNPs) in PLIN1 and seven SNPs in PLIN4 and tested for associations with measures of BMD, bone ultrasound, hip geometry, and height. We found several gender-specific significant associations with the measured traits. The association of PLIN4 SNP rs8887, G>A with height in females trended toward significance after simulation testing (adjusted P = 0.07) and remained significant after simulation testing in the combined-sex model (adjusted P = 0.033). In a large study sample of men and women, we found a significant association between one SNP in PLIN4 and height but not with bone traits, suggesting that PATS family genes are not important in the regulation of bone. Identification of genes that influence human height may lead to a better understanding of the processes involved in growth and development