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Funder: Max-Planck-Gesellschaft, Funder: Bundesministerium für Bildung und Forschung, Neuropsychiatric disorders are increasingly conceptualized as overlapping spectra sharing multi-level neurobiological alterations. However, whether transdiagnostic cortical alterations covary in a biologically meaningful way is currently unknown. Here, we studied co-alteration networks across six neurodevelopmental and psychiatric disorders, reflecting pathological structural covariance. In 12,024 patients and 18,969 controls from the ENIGMA consortium, we observed that co-alteration patterns followed normative connectome organization and were anchored to prefrontal and temporal disease epicenters. Manifold learning revealed frontal-to-temporal and sensory/limbic-to-occipitoparietal transdiagnostic gradients, differentiating shared illness effects on cortical thickness along these axes. The principal gradient aligned with a normative cortical thickness covariance gradient and established a transcriptomic link to cortico-cerebello-thalamic circuits. Moreover, transdiagnostic gradients segregated functional networks involved in basic sensory, attentional/perceptual, and domain-general cognitive processes, and distinguished between regional cytoarchitectonic profiles. Together, our findings indicate that shared illness effects occur in a synchronized fashion and along multiple levels of hierarchical cortical organization.

Objective: To compare the incidence of dyslipidemia in people with HIV receiving integrase inhibitors (INSTI) versus boosted protease inhibitors (PI/b) and nonnucleoside reverse transcriptase inhibitors (NNRTI) within RESPOND consortium of prospective cohorts. Methods: Participants were eligible if they were at least 18 years, without dyslipidemia and initiated or switched to a three-drug antiretroviral therapy (ART)-regimen consisting of either INSTI, NNRTI, or PI/b for the first time, between 1 January 2012 and 31 December 2018. Dyslipidemia was defined as random total cholesterol more than 240 mg/dl, HDL less than 35 mg/dl, triglyceride more than 200 mg/dl, or initiation of lipid-lowering therapy. Poisson regression was used to determine the adjusted incidence rate ratios. Follow-up was censored after 3 years or upon ART-regimen discontinuation or last lipid measurement or 31 December 2019, whichever occurred first. Results: Overall, 4577 people with HIV were eligible (INSTI = 66.9%, PI/b = 12.5%, and NNRTI = 20.6%), 1938 (42.3%) of whom were ART-naive. During 1.7 (interquartile range, 0.6 - 3.0) median years of follow-up, 1460 participants developed dyslipidemia [incidence rate: 191.6 per 1000 person-years, 95% confidence interval (CI) 182.0 - 201.7]. Participants taking INSTI had a lower incidence of dyslipidemia compared with those on PI/b (adjusted incidence rate ratio 0.71; CI 0.59 - 0.85), but higher rate compared with those on NNRTI (1.35; CI 1.15 - 1.58). Compared with dolutegravir, the incidence of dyslipidemia was higher with elvitegravir/cobicistat (1.20; CI 1.00 - 1.43) and raltegravir (1.24; CI 1.02 - 1.51), but lower with rilpivirine (0.77; CI 0.63 - 0.94). Conclusion: In this large consortium of heterogeneous cohorts, dyslipidemia was less common with INSTI than with PI/b. Compared with dolutegravir, dyslipidemia was more common with elvitegravir/cobicistat and raltegravir, but less common with rilpivirine.

OBJECTIVE To compare the incidence of hypertension in people living with HIV receiving integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) versus non-nucleoside reverse transcriptase inhibitors (NNRTIs) or boosted protease inhibitors (PIs) in the RESPOND consortium of HIV cohorts. METHODS Eligible people with HIV were aged ���18��years who initiated a new three-drug ART regimen for the first time (baseline), did not have hypertension, and had at least two follow-up blood pressure (BP) measurements. Hypertension was defined as two consecutive systolic BP measurements ���140��mmHg and/or diastolic BP ���90��mmHg or initiation of antihypertensives. Multivariable Poisson regression was used to determine adjusted incidence rate ratios (aIRRs) of hypertension, overall and in those who were ART na��ve or experienced at baseline. RESULTS Overall, 4606 people living with HIV were eligible (INSTIs��3164, NNRTIs��807, PIs��635). The median baseline systolic BP, diastolic BP, and age were 120 (interquartile range [IQR] 113-130) mmHg, 78 (70-82) mmHg, and 43 (34-50) years, respectively. Over 8380.4 person-years (median follow-up 1.5 [IQR 1.0-2.7]��years), 1058 (23.0%) participants developed hypertension (incidence rate 126.2/1000 person-years, 95% confidence interval [CI] 118.9-134.1). Participants receiving INSTIs had a higher incidence of hypertension than those receiving NNRTIs (aIRR 1.76; 95% CI 1.47-2.11), whereas the incidence was no different in those receiving PIs (aIRR 1.07; 95% CI 0.89-1.29). The results were similar when the analysis was stratified by ART status at baseline. CONCLUSION Although unmeasured confounding and channelling bias cannot be excluded, INSTIs were associated with a higher incidence of hypertension than were NNRTIs, but rates were similar to those of PIs overall, in ART-na��ve and ART-experienced participants within RESPOND.

Several non-mental diseases seem to be associated with an increased risk of ADHD and ADHD seems to be associated with increased risk for non-mental diseases. The underlying trajectories leading to such brain-body co occurrences are often unclear are there direct causal relationships from one disorder to the other, or does the sharing of genetic and/or environmental risk factors lead to their occurring together more frequently or both? Our goal with this narrative review was to provide a conceptual synthesis of the associations between ADHD and non-mental disease across the lifespan. We discuss potential shared pathologic mechanisms, genetic background and treatments in co-occurring diseases. For those co-occurrences for which published studies with sufficient sample sizes exist, meta-analyses have been published by others and we discuss those in detail. We conclude that non-mental diseases are common in ADHD and vice versa and add to the disease burden of the patient across the lifespan. Insufficient attention to such co-occurring conditions may result in missed diagnoses and suboptimal treatment in the affected individuals.

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF, For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

Genome-wide association studies (GWAS) link full genome data to a handful of traits. However, in neuroimaging studies, there is an almost unlimited number of traits that can be extracted for full image-wide big data analyses. Large populations are needed to achieve the necessary power to detect statistically significant effects, emphasizing the need to pool data across multiple studies. Neuroimaging consortia, e.g., ENIGMA and CHARGE, are now analyzing MRI data from over 30,000 individuals. Distributed processing protocols extract harmonized features at each site, and pool together only the cohort statistics using meta analysis to avoid data sharing. To date, such MRI projects have focused on single measures such as hippocampal volume, yet voxelwise analyses (e.g., tensor-based morphometry; TBM) may help better localize statistical effects. This can lead to $10^{13}$1013 tests for GWAS and become underpowered. We developed an analytical framework for multi-site TBM by performing multi-channel registration to cohort-specific templates. Our results highlight the reliability of the method and the added power over alternative options while preserving single site specificity and opening the doors for well-powered image-wide genome-wide discoveries.

BackgroundAutism spectrum disorder (ASD) and obsessive–compulsive disorder (OCD) are neurodevelopmental disorders with considerable overlap in terms of their defining symptoms of compulsivity/repetitive behaviour. Little is known about the extent to which ASD and OCD have common versus distinct neural correlates of compulsivity. Previous research points to potentially common dysfunction in frontostriatal connectivity, but direct comparisons in one study are lacking. Here, we assessed frontostriatal resting-state functional connectivity in youth with ASD or OCD, and healthy controls. In addition, we applied a cross-disorder approach to examine whether repetitive behaviour across ASD and OCD has common neural substrates.MethodsA sample of 78 children and adolescents aged 8–16 years was used (ASD n = 24; OCD n = 25; healthy controls n = 29), originating from the multicentre study COMPULS. We tested whether diagnostic group, repetitive behaviour (measured with the Repetitive Behavior Scale-Revised) or their interaction was associated with resting-state functional connectivity of striatal seed regions.ResultsNo diagnosis-specific differences were detected. The cross-disorder analysis, on the other hand, showed that increased functional connectivity between the left nucleus accumbens (NAcc) and a cluster in the right premotor cortex/middle frontal gyrus was related to more severe symptoms of repetitive behaviour.ConclusionsWe demonstrate the fruitfulness of applying a cross-disorder approach to investigate the neural underpinnings of compulsivity/repetitive behaviour, by revealing a shared alteration in functional connectivity in ASD and OCD. We argue that this alteration might reflect aberrant reward or motivational processing of the NAcc with excessive connectivity to the premotor cortex implementing learned action patterns.

Background: Recently, RBFOX1, a gene encoding an RNA binding protein, has consistently been associated with aggressive and antisocial behavior. Several loci in the gene have been nominally associated with aggression in genome-wide association studies, the risk alleles being more frequent in the general population. We have hence examined the association of four RBFOX1 single nucleotide polymorphisms, previously found related to aggressive traits, with aggressiveness, personality, and alcohol use disorder in birth cohort representative samples. Methods: We used both birth cohorts of the Estonian Children Personality Behavior and Health Study (ECPBHS; original n = 1,238). Aggressiveness was assessed using the Buss-Perry Aggression Questionnaire and the Lifetime History of Aggressiveness structured interview at age 25 (younger cohort) or 33 (older cohort). Big Five personality at age 25 was measured with self-reports and the lifetime occurrence of alcohol use disorder assessed with the MINI interview. RBFOX1 polymorphisms rs809682, rs8062784, rs12921846, and rs6500744 were genotyped in all participants. Given the restricted size of the sample, correction for multiple comparisons was not applied. Results: Aggressiveness was not significantly associated with the RBFOX1 genotype. RBFOX1 rs8062784 was associated with neuroticism and rs809682 with extraversion. Two out of four analyzed RBFOX1 variants, rs8062784 and rs12921846, were associated with the occurrence of alcohol use disorder. Conclusions: In the birth cohort representative sample of the ECPBHS, no association of RBFOX1 with aggressiveness was found, but RBFOX1 variants affected basic personality traits and the prevalence of alcohol use disorder. Future studies on RBFOX1 should consider the moderating role of personality and alcohol use patterns in aggressiveness.

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

The RBFOX1 gene (or A2BP1) encodes a splicing factor important for neuronal development that has been related to autism spectrum disorder and other neurodevelopmental phenotypes. Evidence from complementary sources suggests that this gene contributes to aggressive behavior. Suggestive associations with RBFOX1 have been identified in genome-wide association studies (GWAS) of anger, conduct disorder, and aggressive behavior. Nominal association signals in RBFOX1 were also found in an epigenome-wide association study (EWAS) of aggressive behavior. Also, variants in this gene affect temporal lobe volume, a brain area that is altered in several aggression-related phenotypes. In animals, this gene has been shown to modulate aggressive behavior in Drosophila. RBFOX1 has also been associated with canine aggression and is upregulated in mice that show increased aggression after frustration of an expected reward. Associated common genetic variants as well as rare duplications and deletions affecting RBFOX1 have been identified in several psychiatric and neurodevelopmental disorders that are often comorbid with aggressive behaviors. In this paper, we comprehensively review the cumulative evidence linking RBFOX1 to aggression behavior and provide new results implicating RBFOX1 in this phenotype. Most of these studies (genetic and epigenetic analyses in humans, neuroimaging genetics, gene expression and animal models) are hypothesis-free, which strengthens the validity of the findings, although all the evidence is nominal and should therefore be taken with caution. Further studies are required to clarify in detail the role of this gene in this complex phenotype.

Visual understanding of 3-D environments in real time, at low power, is a huge computational challenge. Often referred to as simultaneous localization and mapping (SLAM), it is central to applications spanning domestic and industrial robotics, autonomous vehicles, and virtual and augmented reality. This paper describes the results of a major research effort to assemble the algorithms, architectures, tools, and systems software needed to enable delivery of SLAM, by supporting applications specialists in selecting and configuring the appropriate algorithm and the appropriate hardware, and compilation pathway, to meet their performance, accuracy, and energy consumption goals. The major contributions we present are: 1) tools and methodology for systematic quantitative evaluation of SLAM algorithms; 2) automated, machine-learning-guided exploration of the algorithmic and implementation design space with respect to multiple objectives; 3) end-to-end simulation tools to enable optimization of heterogeneous, accelerated architectures for the specific algorithmic requirements of the various SLAM algorithmic approaches; and 4) tools for delivering, where appropriate, accelerated, adaptive SLAM solutions in a managed, JIT-compiled, adaptive runtime context.

Contains fulltext : 191895.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 193271pub.pdf (Publisher’s version ) (Open Access) Contains fulltext : 193271pre.pdf (Author’s version preprint ) (Open Access) Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology. 13 p.

We report a new limit on a possible short range spin dependent interaction from the precise measurement of the ratio of Larmor precession frequencies of stored ultracold neutrons and Hg 199 atoms confined in the same volume. The measurement was performed in a ~ 1 µT vertical magnetic holding field with the apparatus searching for a permanent electric dipole moment of the neutron at the Paul Scherrer Institute. A possible coupling between freely precessing polarized neutron spins and unpolarized nucleons of the wall material can be investigated by searching for a tiny change of the precession frequencies of neutron and mercury spins. Such a frequency change can be interpreted as a consequence of a short range spin dependent interaction that could possibly be mediated by axions or axion like particles. The interaction strength is proportional to the \{CP\} violating product of scalar and pseudoscalar coupling constants g S g P . Our result confirms limits from complementary experiments with spin polarized nuclei in a model independent way. Limits from other neutron experiments are improved by up to two orders of magnitude in the interaction range of 10 - 6 lt; ? lt; 10 - 4 m .

OBJECTIVES HIV-positive patients are at an increased risk for chronic kidney disease. However, these data mainly derive from cohorts with a high percentage of African-American patients, representing a specific ethnical risk group for chronic kidney disease. The aim of this study was to estimate the prevalence and risk factors specifically for early signs of kidney dysfunction in a large, predominantly white cohort of HIV patients. DESIGN Cross-sectional study. METHODS Prevalence of low-grade proteinuria was measured by quantitative analysis of urinary protein-to-creatinine ratio (cutoff >70 mg/g) and further differentiated by assessing α1-microglobulin (tubular proteinuria) and albumin-to-creatinine ratio (glomerular proteinuria) of HIV patients attending the University Hospital in Cologne, Germany. Together with standard and HIV-related laboratory findings and medical history, risk factors for each form of proteinuria were identified using multivariate forward selection. RESULTS Of 945 enrolled patients, 55% were identified with low-grade proteinuria, 41% with tubular proteinuria, and 20% with glomerular proteinuria. Older age was a risk factor for all forms of proteinuria in multivariate analysis. Low-grade proteinuria was also associated with concomitant diabetes and exposure to nucleoside reverse transcriptase inhibitor [anytime during HIV infection, not tenofovir (TDF)-specific], whereas tubular proteinuria was linked to current and any exposure to nucleoside reverse transcriptase inhibitor (TDF-specific). Further risk factors for glomerular proteinuria were hypertension and diabetes in this cohort. CONCLUSION Low-grade, glomerular and tubular proteinuria are highly prevalent in this large white HIV cohort. Older age represents a nonmodifiable risk factor for all forms of proteinuria. Glomerular proteinuria is associated with modifiable cardiovascular, but not HIV-related risk factors, whereas tubular proteinuria is linked to TDF exposure.

We have measured the transmission of ultra-cold neutrons (UCN) through tubes coated on the inside with materials of high optical potentials. The best transmission value, T, normalised to 1 m long UCN guides was obtained with a beryllium coated quartz guide, T=(99.0±1.0)%. Furthermore, excellent transmission coefficients were found for (i) a glass tube coated with NiMo(88/12), T=(97.3 ±0.6)%, (ii) a NiMo(85/15) guide made by the replication technique, T=(97.1 ±0.8)% and (iii) a glass guide coated with NiMo(82/18), T=(96.3 ±2.1)%. The results demonstrate that UCN guides made from coated glass tubes have the same excellent transmission properties as those produced with the replication technique. They are, however, significantly cheaper.

Item does not contain fulltext The brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT) genes are relevant candidates for depression. Variation in these genes is associated with stress sensitivity and depressotypic cognitive biases. The interaction between genes and stressful events is considered as an important mechanism in the development of depression. This study examined the effects of the BDNF and COMT genes on biased processing and the interaction with childhood stress in vulnerable individuals. A total of 198 remitted depressed individuals performed an n-back task with emotional facial stimuli (happy and sad). Childhood events were measured with a questionnaire. Genotype by childhood events interactions were analyzed for happy and sad expressions for BDNF (Val66Met; rs6265) and COMT (Val158Met; rs4680), individually and combined. BDNF and COMT both interacted significantly (P = 0.006 and P = 0.014, respectively) with childhood trauma on reaction time for happy faces. For both genes, Met-carriers with childhood trauma showed less positive bias for happy faces than those without childhood trauma. Val-carriers did not show a differential bias. Individuals with childhood trauma and 3 or 4 risk alleles (BDNF and COMT combined) showed less positive bias than those without childhood trauma (P = 0.011). The BDNF x COMT x childhood trauma interaction yielded a P = 0.055, but had limited power. A potential weakness is the measurement method of the childhood events, as negative bias might have affected participants' recall. Our findings endorse the association of BDNF and COMT with stress and depression and provide a possible intermediate, i.e. biased processing of positive information. Tailoring treatment to specific risk profiles based on genetic susceptibility and childhood stress could be promising. 9 p.

Contains fulltext : 174503pub.pdf (Publisher’s version ) (Closed access) INTRODUCTION: Reward processing is a key aspect of cognitive control processes, putatively instantiated by mesolimbic and mesocortical brain circuits. Deficient signaling within these circuits has been associated with psychopathology. We applied a network discovery approach to assess specific functional networks associated with reward processing in participants with attention-deficit/hyperactivity disorder (ADHD). METHODS: To describe task-related processes in terms of integrated functional networks, we applied independent component analysis (ICA) to task response maps of 60 healthy participants who performed a monetary incentive delay (MID) task. The resulting components were interpreted on the basis of their similarity with group-level task responses as well as their similarity with brain networks derived from resting state fMRI analyses. ADHD-related effects on network characteristics including functional connectivity and communication between networks were examined in an independent sample comprising 150 participants with ADHD and 48 healthy controls. RESULTS: We identified 23 components to be associated with 4 large-scale functional networks: the default-mode, visual, executive control, and salience networks. The salience network showed a specific association with reward processing as well as the highest degree of within-network integration. ADHD was associated with decreased functional connectivity between the salience and executive control networks as well as with peripheral brain regions. CONCLUSIONS: Reward processing as measured with the MID task involves one reward-specific and three general functional networks. Participants with ADHD exhibited alterations in connectivity of both the salience and executive control networks and associated brain regions during task performance. Hum Brain Mapp 38:2359-2369, 2017. (c) 2017 Wiley Periodicals, Inc.

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case-only sample (n=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (P=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (P=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD.

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Item does not contain fulltext BACKGROUND: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) share about 50-72% of their genetic factors, which is the most likely explanation for their frequent co-occurrence within the same patient or family. An additional or alternative explanation for the co-occurrence may be (cross-)assortative mating, e.g., the tendency to choose a partner that is similar or dissimilar to oneself. Another issue is that of parent-of-origin effect which refers to the possibility of parents differing in the relative quantity of risk factors they transmit to the offspring. The current study sets out to examine (cross-)assortative mating and (cross-)parent-of-origin effects of ASD and ADHD in parents of children with either ASD or ASD with ADHD diagnosis. METHODS: In total, 121 families were recruited in an ongoing autism-ADHD family genetics project. Participating families consisted of parents and at least one child aged between 2 and 20 years, with either autistic disorder, Asperger disorder or PDD-NOS, and one or more biological siblings. All children and parents were carefully screened for the presence of ASD and ADHD. RESULTS: No correlations were found between maternal and paternal ASD and ADHD symptoms. Parental ASD and ADHD symptoms were predictive for similar symptoms in the offspring, but with maternal hyperactive-impulsive symptoms, but not paternal symptoms, predicting similar symptoms in daughters. ASD pathology in the parents was not predictive for ADHD pathology in the offspring, but mother's ADHD pathology was predictive for offspring ASD pathology even when corrected for maternal ASD pathology. CONCLUSIONS: Cross-assortative mating for ASD and ADHD does not form an explanation for the frequent co-occurrence of these disorders within families. Given that parental ADHD is predictive of offspring' ASD but not vice versa, risk factors underlying ASD may overlap to a larger degree with risk factors underlying ADHD than vice versa. However, future research is needed to clarify this issue.

Item does not contain fulltext The topic of this article is sexual violence in context with war-like conflicts in the former Yugoslavia and Rwanda. The fundamental categories of sexual violence in war-like conflicts are described. The authors discuss the types of sexual violence as defined in the report of the UN Commission of Experts on the war-like conflicts in the former Yugoslavia. Four criminal trials were evaluated: three held before the International Criminal Tribunal for the Former Yugoslavia (ICTY) in The Hague/Netherlands and one before the International Criminal Tribunal for Rwanda (ICTR) in Arusha/Tansania. The defendants were found guilty of torture, crime against humanity and genocide. Potential procedures with respect to similar crimes in current or prospective conflicts are discussed. An alternative may be the assignment of medical personnel (for example of the German Federal Armed Forces). Finally, the post-war cooperation between the Institute of Legal Medicine at the University Medical Centre of Hamburg-Eppendorf as well as the medical and government institutions in Rwanda is presented, which has been going on since 2005.

Contains fulltext : 96794.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To examine the relationship between obesity and depressive symptoms taking into account different measures for obesity (body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR)) and different depressive symptom clusters. DESIGN: Cross-sectional population-based survey. SETTING: Baseline data of the Nijmegen Biomedical Study. PARTICIPANTS: One thousand two hundred eighty-four persons aged 50 to 70. MEASUREMENTS: Obesity (BMI, WC, and WHR) and depressive symptoms were measured, the latter using the Beck Depression Inventory (BDI). Principal components analysis of the BDI items yielded two factors, one representing a cognitive-affective symptom cluster and the other a somatic-affective symptom cluster. Multiple regression analyses corrected for confounders were conducted for each measure of obesity, with separate models testing the BDI sum score and the depression symptom clusters. RESULTS: BMI was significantly associated with BDI sum score (beta=0.12, P

Contains fulltext : 71322.pdf (Publisher’s version ) (Closed access) In this study, we attempted to confirm genetic linkage to developmental dyslexia and reading-related quantitative traits of loci that have been shown to be associated with dyslexia in previous studies. In our sample of 108 Dutch nuclear families, the categorical trait showed strongest linkage to 1p36 (NPL-LOD = 2.1). LOD scores for quantitative traits word-reading, non-word reading, and rapid naming peaked near the same location as the categorical trait, as well as on chromosome 2. Non-word repetition showed little phenotypic correlation with dyslexia or with the other quantitative traits, and this trait showed linkage peaks on 11p and 15q. No evidence for linkage to 6p22-23 was found for this set of families. Comparison of our results and literature data shows that loci link to different phenotypes in different samples. The mutual connections of these traits and their relation to developmental dyslexia remain elusive.

Item does not contain fulltext BACKGROUND: Major depressive disorder (MDD) aggregates in families and is associated with high rates of lifetime axis-I comorbidity. This study examined whether familiality of MDD is associated with the presence of specific comorbid disorders, which might be an important factor to be taken into account in MDD treatment and research into MDD etiology. METHODS: A population sample was divided into subjects with familial (f-MDD; n=432) and nonfamilial MDD (nf-MDD; n=454). Since, more comorbidity was expected in clinical cases, a clinical sample with f-MDD (n=120) was also studied. Subjects were assessed with the Composite International Diagnostic Interview and family history methods. Binary logistic regression analyses were carried out to examine the influence of familiality of MDD on comorbidity. Analyses were adjusted for potential confounders, including MDD characteristics such as severity and age of onset. RESULTS: Dysthymia, anxiety disorders, and alcohol use disorders were significantly more prevalent in subjects with f-MDD than in subjects with nf-MDD. Clinical f-MDD was associated with more anxiety disorders and fewer alcohol use disorders than population f-MDD. After adjustment for MDD characteristics including age at onset, severity, and disease course, comorbid disorders remained more prevalent in f-MDD than in nf-MDD. LIMITATIONS: The instruments used in the population and the clinical samples were not identical, however, they were comparable to a substantial degree. CONCLUSIONS: F-MDD, especially in clinical cases, appears to increase the risk of development of comorbid disorders, regardless of MDD characteristics. The link between familiality and comorbidity is important because it will aid a better understanding of the MDD phenotype, and it contributes to planning of effective treatment and to molecular genetic studies. 8 p.

The Wellcome Trust, MRC and Action Medical Research have provided ADHD research support for AT, PH, JM, NW, MJO, MCO; we also acknowledge support from NIH grants R1 3MH059126, R0 1MH62873 and R0 1MH081803 to Dr SV Faraone. Dr E Mick received funding through the UMass Center for Clinical and Translational Science (P30HD004147) supported by the NIH. A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 × 10-4) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders. Publisher PDF

Contains fulltext : 47960.pdf (Publisher’s version ) (Closed access) Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by concentration problems, hyperactivity and impulsivity. Disturbances in dopamine and/or noradrenalin neurotransmission are probably the underlying pathophysiological mechanisms of ADHD. Around 80% of variants of the phenotype can be ascribed to hereditary factors. There are various chromosomal loci containing ADHD genes. They partially overlap the loci found in linkage studies on dyslexia and autism. It seems likely that a number of genetic variants, each with a small effect size, in combination with gene-environment interactions predispose to ADHD. There is a high degree of phenotypical heterogeneity among people with ADHD. Finding endophenotypes may improve the power of genetic studies. Endophenotypes are specific expressions of the underlying pathophysiology, intermediate between gene and phenotype. Neuro-imaging studies in children with ADHD have indicated abnormalities in frontostriatal, temporal and cerebellar volume. Unaffected brothers and sisters show the same cerebral abnormalities, but not the cerebellar abnormalities. These brain abnormalities together with specific neuropsychological features could be ADHD endophenotypes.

Contains fulltext : 141121.pdf (Publisher’s version ) (Open Access) Attention-deficit/hyperactivity disorder (ADHD) is accompanied by impairments in cognitive control, such as task-switching deficits. We investigated whether such problems, and their remediation by medication, reflect abnormal reward motivation and associated striatal dopamine transmission in ADHD. We used functional genetic neuroimaging to assess the effects of dopaminergic medication and reward motivation on task-switching and striatal BOLD signal in 23 adults with ADHD, ON and OFF methylphenidate, and 26 healthy controls. Critically, we took into account interindividual variability in striatal dopamine by exploiting a common genetic polymorphism (3'-UTR VNTR) in the DAT1 gene coding for the dopamine transporter. The results showed a highly significant group by genotype interaction in the striatum. This was because a subgroup of patients with ADHD showed markedly exaggerated effects of reward on the striatal BOLD signal during task-switching when they were OFF their dopaminergic medication. Specifically, patients carrying the 9R allele showed a greater striatal signal than healthy controls carrying this allele, whereas no effect of diagnosis was observed in 10R homozygotes. Aberrant striatal responses were normalized when 9R-carrying patients with ADHD were ON medication. These pilot data indicate an important role for aberrant reward motivation, striatal dopamine and interindividual genetic differences in cognitive processes in adult ADHD. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.

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Contains fulltext : 152880.pdf (Publisher’s version ) (Open Access) Cocaine reward and reinforcing effects are mediated mainly by dopaminergic neurotransmission. In this study, we aimed at evaluating gene expression changes induced by acute cocaine exposure on SH-SY5Y-differentiated cells, which have been widely used as a dopaminergic neuronal model. Expression changes and a concomitant increase in neuronal activity were observed after a 5 muM cocaine exposure, whereas no changes in gene expression or in neuronal activity took place at 1 muM cocaine. Changes in gene expression were identified in a total of 756 genes, mainly related to regulation of transcription and gene expression, cell cycle, adhesion and cell projection, as well as mitogen-activeated protein kinase (MAPK), CREB, neurotrophin and neuregulin signaling pathways. Some genes displaying altered expression were subsequently targeted with predicted functional single-nucleotide polymorphisms (SNPs) in a case-control association study in a sample of 806 cocaine-dependent patients and 817 controls. This study highlighted associations between cocaine dependence and five SNPs predicted to alter microRNA binding at the 3'-untranslated region of the NFAT5 gene. The association of SNP rs1437134 with cocaine dependence survived the Bonferroni correction for multiple testing. A functional effect was confirmed for this variant by a luciferase reporter assay, with lower expression observed for the rs1437134G allele, which was more pronounced in the presence of hsa-miR-509. However, brain volumes in regions of relevance to addiction, as assessed with magnetic resonance imaging, did not correlate with NFAT5 variation. These results suggest that the NFAT5 gene, which is upregulated a few hours after cocaine exposure, may be involved in the genetic predisposition to cocaine dependence.

Contains fulltext : 127593.pdf (Publisher’s version ) (Open Access) The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way. 30 p.

The small GTPase Rap1 is highly expressed in human neutrophils, but its function is largely unknown. Using the Rap1-binding domain of RalGDS (RalGDS-RBD) as an activation-specific probe for Rap1, we have investigated the regulation of Rap1 activity in primary human neutrophils. We found that a variety of stimuli involved in neutrophil activation, including fMet-Leu-Phe (fMLP), platelet-activating factor (PAF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IgG-coated particles, induce a rapid and transient Rap1 activation. In addition, we found that Rap1 is normally activated in neutrophils from chronic granulomatous disease patients that lack cytochrome b558 or p47phox and have a defective NADPH oxidase system. From these results we conclude that in neutrophils Rap1 is activated independently of respiratory burst induction. Finally, we found that Rap1 is activated by both the Ca2+ ionophore ionomycin and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), indicating that phospholipase C (PLC) activation leading to elevated levels of intracellular free Ca2+ and diacylglycerol (DAG) can mediate Rap1 activation. However, inhibition of PLC and Ca2+ depletion only marginally affected fMLP-induced Rap1 activation, suggesting that additional pathways may control Rap1 activation.© 1998 by The American Society of Hematology.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field. Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders). National Institute of Mental Health N01 MH900001 MH074027 1U24MH081810 R01 MH078075 Eli Lilly and Company Pritzker Neuropsychiatric Disorders Research Fund L.L.C. Massachusetts General Hospital in Boston, MA (NIMH) 2N01MH080001-001 Wellcome Trust 076113 085475 075491/Z/04 085475/B/08/Z 085475/Z/08/Z Medical Research Council G0601030 Anthony P Monaco, PI, University of Oxford National Genome Research Network of the German Federal Ministry of Education and Research (BMBF) 01GS08144 01GS08147 Centre of Excellence for Complex Disease Genetics of the Academy of Finland 213506 129680 Biocentrum Helsinki Foundation Research Program for Molecular Medicine, Faculty of Medicine, University of Helsinki Stanley Medical Research Institute Danish Council for Strategic Research 2101-07-0059 H Lundbeck A/S; the Research Council of Norway 163070/V50 Danish Medical Research Council South-East Norway Health Authority 2004-123 Medical Research Council Ministerio de Sanidad y Consumo, Spain PI081522 Xunta de Galicia 08CSA005208PR Swedish Research Council Wellcome Trust Case Control Consortium 2 Max Planck Society; Saarland University T6 03 10 00-45 Netherlands Foundation for Brain Research (Hersenstichting) 2008(1).34 2006-037761 PIAP-GA-2008-218251 HEALTH-F2-2009-223423 HEALTH-F4-2009-242257 info:eu-repo/grantAgreement/EC/FP7/218251

Contains fulltext : 133486.pdf (Publisher’s version ) (Open Access) The PCLO rs2522833 candidate polymorphism for depression has been associated to monoaminergic neurotransmission. In healthy and currently depressed individuals, the polymorphism has been found to affect activation of brain areas during memory processing, but no direct association of PCLO with memory bias was found. We hypothesized that the absence of this association might have been obscured by current depressive symptoms or genetically driven individual differences in reactivity to stressful events. Experiencing stressful childhood events fosters dysfunctional assumptions that are related to cognitive biases, and may modulate the predisposition for depression via epigenetic effects. The association between PCLO and memory bias, as well as interaction between PCLO and childhood events was studied in patients remitted from depression (N = 299), as well as a sample of healthy individuals (N = 157). The participants performed an emotional verbal memory task after a sad mood induction. Childhood trauma and adversity were measured with a questionnaire. The Genotype main effect, and Genotype by Childhood Events interaction were analyzed for memory bias in both samples. PCLO risk allele carrying remitted depressed patients did not show more negatively biased memory than non-risk allele carriers, not even patients with stressful childhood events. A similar pattern of results was found in healthy individuals. Memory bias may not be strongly associated with the PCLO rs2522833 polymorphism. We did not find any support for the PCLO-childhood events interaction, but the power of our study was insufficient to exclude this possibility. 6 p.

Rongelap Island was the home of Marshallese people numbering less than 120 in 1954; 67 were on the island and severely exposed to radioactive fallout from an atomic weapons test in March of that year. Those resident on Rongelap were evacuated 50 h after the test, returned 3 y later, then voluntarily left their home island in 1985 due to their ongoing fear of radiation exposure from residual radioactive contamination. Following international negotiations in 1991, a Memorandum of Understanding (MOU) was signed in early 1992 between the Republic of the Marshall Islands Government, the Rongelap Atoll Local Government, the U.S. Department of Energy, and the U.S. Department of the Interior. In this MOU it was agreed that the Republic of the Marshall Islands, with the aid of the U.S. Department of Energy, would carry out independent dose assessments for the purpose of assisting and advising the Rongelap community on radiological issues related to a safe resettlement of Rongelap. The MOU enacted two action levels which were agreed to be used to establish whether mitigation should be considered as a condition for resettlement of Rongelap Island: (1) no individual should receive an annual dose in the future of 1 mSv or more, above that from natural background radiation, assuming that his/her diet consists of only locally produced foods, and (2) the total surface soil concentration of plutonium and other transuranic elements must be less than 629 Bq kg(-1) (averaged over the top 5 cm). Environmental radiological data and dietary information were collected over two years (1992-1993) for the purpose of predicting future potential doses to Rongelapese who might resettle. In 1994, four independent assessments were reported, including one from each of the following entities: Marshall Islands Nationwide Radiological Study; Lawrence Livermore National Laboratory; an independent advisor from the United Kingdom (MCT); and a committee of the National Research Council. All four assessments concluded that possibly more than 25% of the adult population could exceed the 1 mSv y(-1) dose level based on strict utilization of a local food diet. The purpose of this report is to summarize the methodology, assumptions, and findings from each of four assessments; to summarize the recommendations related to mitigation and resettlement options; to discuss unique programmatic aspects of the study; and to consider the implications of the findings to the future of the Rongelap people.

Item does not contain fulltext Genetic factors and childhood adverse experiences contribute to the vulnerability to alcohol dependence. However, empirical data on the interplay between specific genes and adverse experiences are few. The COMT Val158Met and DRD2/ANKK1 Taq1A genotypes have been suggested to affect both stress sensitivity and the risk for alcohol dependence. This study tested the hypothesis that genetic variation in COMT Val158Met and DRD2/ANKK1 Taq1A interacts with childhood adverse experiences to predict alcohol dependence. Male abstinent alcohol-dependent patients (n = 110) and age-matched healthy male controls (n = 99) were genotyped for the COMT Val158Met and the DRD2/ANKK1 Taq1A genotypes. Childhood adverse events were measured using three self-report questionnaires. Alcohol dependence severity, age of onset and duration of alcohol dependence were analyzed as secondary outcome measures. Statistical analysis involved logistic regression analysis and analysis of variance. Alcohol-dependent patients reported increased childhood adversity. The interaction between childhood adversity and the COMT Val158Met genotype added significantly to the prediction model. This gene-environment interaction was confirmed in the analysis of the secondary outcome measures, i.e. alcohol dependence severity, age of onset and duration of alcohol dependence. The DRD2/ANKK1 Taq1A genotype was not related to alcohol dependence, nor did it interact with childhood adversity in predicting alcohol dependence. This study provides evidence for a gene-environment interaction in alcohol dependence, in which an individual's sensitivity to childhood adverse experience is moderated by the COMT genotype. Exposed carriers of a low-activity Met allele have a higher risk to develop severe alcohol dependence than individuals homozygous for the Val allele.

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Contains fulltext : 174906.pdf (Publisher’s version ) (Closed access) AIM: To examine the relationship between a childhood diagnosis of attention deficit hyperactivity disorder (ADHD) with or without oppositional defiant disorder (ODD)/conduct disorder (CD) and the development of later alcohol/drug use disorder [psychoactive substance use disorder (PSUD)] and nicotine dependence in a large European sample of ADHD probands, their siblings and healthy control subjects. PARTICIPANTS, DESIGN AND SETTING: Subjects (n = 1017) were participants in the Belgian, Dutch and German part of the International Multicenter ADHD Genetics (IMAGE) study. IMAGE families were identified through ADHD probands aged 5-17 years attending out-patient clinics, and control subjects from the same geographic areas. After a follow-up period (mean: 4.4 years) this subsample was re-assessed at a mean age of 16.4 years. MEASUREMENTS: PSUD and nicotine dependence were assessed using the Diagnostic Interview Schedule for Children, Alcohol Use Disorders Identification Test, Drug Abuse Screening Test and Fagerstrom test for Nicotine Dependence. FINDINGS: The ADHD sample was at higher risk of developing PSUD [hazard ratio (HR) = 1.77, 95% confidence interval (CI) = 1.05-3.00] and nicotine dependence (HR = 8.61, 95% CI = 2.44-30.34) than healthy controls. The rates of these disorders were highest for ADHD youth who also had CD, but could not be accounted for by this comorbidity. We did not find an increased risk of developing PSUD (HR = 1.18, 95% CI = 0.62-2.27) or nicotine dependence (HR = 1.89, 95% CI = 0.46-7.77) among unaffected siblings of ADHD youth. CONCLUSIONS: A childhood diagnosis of attention deficit hyperactivity disorder is a risk factor for psychoactive substance use disorder and nicotine dependence in adolescence and comorbid conduct disorder, but not oppositional defiant disorder, further increases the risk of developing psychoactive substance use disorder and nicotine dependence.

Item does not contain fulltext 5th Annual Neurobiology of Language Conference, 8 november 2013 San Diego, California, USA : [s.n.]

Schizophrenia risk gene ZNF804A does not influence macroscopic brain structure: an MRI study in 892 volunteers

Background: Twin studies using both clinical and population-based samples suggest that the frequent co-occurrence of attention deficit hyperactivity disorder (ADHD) and reading ability/disability (RD) is largely driven by shared genetic influences. While both disorders are associated with lower IQ, recent twin data suggest that the shared genetic variability between reading difficulties and ADHD inattention symptoms is largely independent from genetic influences contributing to general cognitive ability. The current study aimed to extend the previous findings that were based on rating scale measures in a population sample by examining the generalisability of the findings to a clinical population, and by measuring reading difficulties both with a rating scale and with an objective task. This study investigated the familial relationships between ADHD, reading difficulties and IQ in a sample of individuals diagnosed with ADHD combined type, their siblings and control sibling pairs. Methods: Multivariate familial models were run on data from 1,789 individuals at ages 6-19. Reading difficulties were measured with both rating scale and an objective task. IQ was obtained using the Wechsler Intelligence Scales (WISC-III/WAIS-III). Results: Significant phenotypic (.2-.4) and familial (.3-.5) correlations were observed among ADHD, reading difficulties and IQ. Yet, 53%-72% of the overlapping familial influences between ADHD and reading difficulties were not shared with IQ. Conclusions: Our finding that familial influences shared with general cognitive ability, although present, do not account for the majority of the overlapping familial influences on ADHD and reading difficulties extends previous findings from a population-based study to a clinically ascertained sample with combined type ADHD. © 2012 Association for Child and Adolescent Mental Health.

Item does not contain fulltext OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. METHOD: The authors performed a genome-wide analysis of large, rare CNVs (100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. CONCLUSIONS: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5-3.6), this locus could be an important contributor to ADHD etiology. 01 februari 2012

Item does not contain fulltext OBJECTIVE: A major motivation for seeking disease-associated genetic variation is to identify novel risk processes. Although rare copy number variants (CNVs) appear to contribute to attention deficit hyperactivity disorder (ADHD), common risk variants (single-nucleotide polymorphisms [SNPs]) have not yet been detected using genome-wide association studies (GWAS). This raises the concern as to whether future larger-scale, adequately powered GWAS will be worthwhile. The authors undertook a GWAS of ADHD and examined whether associated SNPs, including those below conventional levels of significance, influenced the same biological pathways affected by CNVs. METHOD: The authors analyzed genome-wide SNP frequencies in 727 children with ADHD and 5,081 comparison subjects. The gene sets that were enriched in a pathway analysis of the GWAS data (the top 5% of SNPs) were tested for an excess of genes spanned by large, rare CNVs in the children with ADHD. RESULTS: No SNP achieved genome-wide significance levels. As previously reported in a subsample of the present study, large, rare CNVs were significantly more common in case subjects than comparison subjects. Thirteen biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related and CNS development pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS. CONCLUSIONS: Both common and rare genetic variants appear to be relevant to ADHD and index-shared biological pathways. 01 februari 2012

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BackgroundNegative memory bias is thought to be one of the main cognitive risk and maintenance factors for depression, but its neural substrates are largely unknown. Here, we studied whether memory bias is related to amygdala and hippocampal volume, two structures that are critical for emotional memory processes and that show consistent volume alterations in depression.MethodStructural magnetic resonance imaging (MRI) was carried out in 272 healthy participants (62% female, 18–50 years old). All images were acquired on 1.5 T Siemens MRI scanners. Automatic segmentation of amygdala and hippocampus was performed using the FIRST module of FSL. Negative memory bias was assessed by the self-referent encoding/evaluation test.ResultsNegative memory bias was associated with larger amygdala (p=0.042) and smaller hippocampal (p=0.029) volumes. In additional analyses, we found that, compared with the associations found with hippocampus and amygdala volume separately, a stronger association was found between negative memory bias and the ratio of amygdala:hippocampus volume (p=0.021).ConclusionsIn non-depressed subjects we found that larger amygdala and smaller hippocampal volumes are associated with negative memory bias. This suggests that an increased amygdala:hippocampus volume ratio plays a role in cognitive vulnerability often seen in individuals with high risk for depression and that these structural brain differences may pre-date the onset of depression.

A permanent electric dipole moment of fundamental spin-1/2 particles violates both parity (P) and time re- versal (T) symmetry, and hence, also charge-parity (CP) symmetry since there is no sign of CPT-violation. The search for a neutron electric dipole moment (nEDM) probes CP violation within and beyond the Stan- dard Model. The experiment, set up at the Paul Scherrer Institute (PSI), an improved, upgraded version of the apparatus which provided the current best experimental limit, dn < 2.9E-26 ecm (90% C.L.), by the RAL/Sussex/ILL collaboration: Baker et al., Phys. Rev. Lett. 97, 131801 (2006). In the next two years we aim to improve the sensitivity of the apparatus to sigma(dn) = 2.6E-27 ecm corresponding to an upper limit of dn < 5E-27 ecm (95% C.L.), in case for a null result. In parallel the collaboration works on the design of a new apparatus to further increase the sensitivity to sigma(dn) = 2.6E-28 ecm., APS Division for particles and fields, Conference Proceedings, Two figures

Item does not contain fulltext Gene-brain structure associations of 3 recently discovered risk genes for Alzheimer's disease, CLU (rs11136000C>T), CR1 (rs6656401G>A), and PICALM (rs3851179G>A), were investigated in 2 independent cohorts of young healthy adults (n = 430 and n = 492, respectively). We assessed structural differences in 2 core structures of Alzheimer pathology, entorhinal cortex and hippocampus, by voxel-based morphometry using high-resolution magnetic resonance imaging (MRI) data. For CLU and PICALM no significant genotype-related differences in local gray matter volume were found. CR1 risk allele (A) carriers showed smaller local gray matter volume in the entorhinal cortex, as confirmed in both cohorts. This association, apparent in young healthy adults, might mediate susceptibility for Alzheimer's disease later in life.