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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.

This White Paper, prepared for the Fundamental Symmetries, Neutrons, and Neutrinos Town Meeting related to the 2023 Nuclear Physics Long Range Plan, makes the case for double beta decay as a critical component of the future nuclear physics program. The major experimental collaborations and many theorists have endorsed this white paper., white paper submitted for the Fundamental Symmetries, Neutrons, and Neutrinos Town Meeting in support of the US Nuclear Physics Long Range Planning Process

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.

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.

Rationale Compulsivity often develops during childhood and is associated with elevated glutamate levels within the frontostriatal system. This suggests that anti-glutamatergic drugs, like memantine, may be an effective treatment. Objective Our goal was to characterize the acute and chronic effect of memantine treatment on compulsive behavior and frontostriatal network structure and function in an adolescent rat model of compulsivity. Methods Juvenile Sprague–Dawley rats received repeated quinpirole, resulting in compulsive checking behavior (n = 32; compulsive) or saline injections (n = 32; control). Eight compulsive and control rats received chronic memantine treatment, and eight compulsive and control rats received saline treatment for seven consecutive days between the 10th and 12th quinpirole/saline injection. Compulsive checking behavior was assessed, and structural and functional brain connectivity was measured with diffusion MRI and resting-state fMRI before and after treatment. The other rats received an acute single memantine (compulsive: n = 12; control: n = 12) or saline injection (compulsive: n = 4; control: n = 4) during pharmacological MRI after the 12th quinpirole/saline injection. An additional group of rats received a single memantine injection after a single quinpirole injection (n = 8). Results Memantine treatment did not affect compulsive checking nor frontostriatal structural and functional connectivity in the quinpirole-induced adolescent rat model. While memantine activated the frontal cortex in control rats, no significant activation responses were measured after single or repeated quinpirole injections. Conclusions The lack of a memantine treatment effect in quinpirole-induced compulsive adolescent rats may be partly explained by the interaction between glutamatergic and dopaminergic receptors in the brain, which can be evaluated with functional MRI.

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.

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.

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.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3–96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders. The author list between I.A. and M.Z. is in alphabetic order. The authors were funded by the Research Council of Norway (276082 LifespanHealth (T.K.), 213837 (O.A.A), 223273 NORMENT (O.A.A.), 204966 (L.T.W.), 229129 (O.A.A.), 249795 (L.T.W.), 273345 (L.T.W.) and 283798 SYNSCHIZ (O.A.A.)), the South-Eastern Norway Regional Health Authority (2013-123 (O.A.A.), 2014-097 (L.T.W.), 2015-073 (L.T.W.) and 2016083 (L.T.W.)), Stiftelsen Kristian Gerhard Jebsen (SKGJ-MED-008), the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC Starting Grant, Grant agreement No. 802998 BRAINMINT (L.T.W.)), NVIDIA Corporation GPU Grant (T.K.), and the European Commission 7th Framework Programme (602450, IMAGEMEND (A.M.-L.)).

Contains fulltext : 202693.pdf (Publisher’s version ) (Open Access) Schizophrenia is a severe mental disorder characterized by numerous subtle changes in brain structure and function. Machine learning allows exploring the utility of combining structural and functional brain magnetic resonance imaging (MRI) measures for diagnostic application, but this approach has been hampered by sample size limitations and lack of differential diagnostic data. Here, we performed a multi-site machine learning analysis to explore brain structural patterns of T1 MRI data in 2668 individuals with schizophrenia, bipolar disorder or attention-deficit/ hyperactivity disorder, and healthy controls. We found reproducible changes of structural parameters in schizophrenia that yielded a classification accuracy of up to 76% and provided discrimination from ADHD, through it lacked specificity against bipolar disorder. The observed changes largely indexed distributed grey matter alterations that could be represented through a combination of several global brain-structural parameters. This multi-site machine learning study identified a brain-structural signature that could reproducibly differentiate schizophrenia patients from controls, but lacked specificity against bipolar disorder. While this currently limits the clinical utility of the identified signature, the present study highlights that the underlying alterations index substantial global grey matter changes in psychotic disorders, reflecting the biological similarity of these conditions, and provide a roadmap for future exploration of brain structural alterations in psychiatric patients.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits. Postprint

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

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)

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. © 2018 American Association for the Advancement of Science. All rights reserved.

Background Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. Methods We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls). Results Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98–1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11–1.18], p = 1.5E-15). Conclusions Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.

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.

Contains fulltext : 153979.pdf (Publisher’s version ) (Closed access) Brain white matter (WM) tracts, playing a vital role in the communication between brain regions, undergo important maturational changes during adolescence and young adulthood, a critical period for the development of nicotine dependence. Attention-deficit/hyperactivity disorder (ADHD) is associated with increased smoking and widespread WM abnormalities, suggesting that the developing ADHD brain might be especially vulnerable to effects of smoking. This study aims to investigate the effect of smoking on (WM) microstructure in adolescents and young adults with and without ADHD. Diffusion tensor imaging was performed in an extensively phenotyped sample of nonsmokers (n = 95, 50.5% ADHD), irregular smokers (n = 41, 58.5% ADHD), and regular smokers (n = 50, 82.5% ADHD), aged 14-24 years. A whole-brain voxelwise approach investigated associations of smoking, ADHD and their interaction, with WM microstructure as measured by fractional anisotropy (FA) and mean diffusivity (MD). Widespread alterations in FA and MD were found for regular smokers compared to irregular and nonsmokers, mainly located in the corpus callosum and WM tracts surrounding the basal ganglia. Several regions overlapped with regions of altered FA for ADHD versus controls, albeit in different directions. Irregular and nonsmokers did not differ, and ADHD and smoking did not interact. Results implicate that smoking and ADHD have independent effects on WM microstructure, and possibly do not share underlying mechanisms. Two mechanisms may play a role in the current results. First, smoking may cause alterations in WM microstructure in the maturing brain. Second, pre-existing WM microstructure differences possibly reflect a risk factor for development of a smoking addiction. Hum Brain Mapp 36:1180-1189, 2015. (c) 2014 Wiley Periodicals, Inc.

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 .

High-precision measurements of the proton radius from laser spectroscopy of muonic hydrogen demonstrated up to six standard deviations smaller values than obtained from electron-proton scattering and hydrogen spectroscopy. The status of this discrepancy, which is known as the proton radius puzzle will be discussed in this paper, complemented with the new insights obtained from spectroscopy of muonic deuterium., Moriond 2017 conference, 8 pages, 4 figures

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 : 169966.pdf (Publisher’s version ) (Closed access) BACKGROUND: Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady-state 6-methylmercaptopurine ribonucleotide (6-MMPR) metabolite concentrations. AIM: To determine the predictive value of 6-MMPR concentrations 1 week after treatment initiation (T1) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment. METHODS: The cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomised-controlled trial evaluating pre-treatment thiopurine S-methyltransferase genotype testing (ClinicalTrials.gov NCT00521950). Blood samples for metabolite assessment were collected at T1. Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase >/=5. RESULTS: Forty-seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6-MMPR threshold of 3615 pmol/8 x 108 erythrocytes was defined. Analysis of patients on stable thiopurine dose (n = 174) showed that those exceeding the 6-MMPR threshold were at increased risk of hepatotoxicity: OR = 3.8 (95% CI: 1.8-8.0). Age, male gender and BMI were significant determinants. A predictive algorithm was developed based on these determinants and the 6-MMPR threshold to assess hepatotoxicity risk [AUC = 0.83 (95% CI: 0.75-0.91)]. 6-MMPR concentrations above the threshold also correlated with gastrointestinal complaints: OR = 2.4 (95% CI: 1.4-4.3), and general malaise: OR = 2.0 (95% CI: 1.1-3.7). CONCLUSIONS: In more than 80% of patients, thiopurine-induced hepatotoxicity could be explained by elevated T1 6-MMPR concentrations and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure.

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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BackgroundAttention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently co-occurring and highly heritable mental health conditions. We hypothesized that BPD cases with an early age of onset (?21 years old) would be particularly likely to show genetic covariation with ADHD.MethodsGenome-wide association study data were available for 4609 individuals with ADHD, 9650 individuals with BPD (5167 thereof with early-onset BPD), and 21,363 typically developing controls. We conducted a cross-disorder genome-wide association study meta-analysis to identify whether the observed comorbidity between ADHD and BPD could be due to shared genetic risks.ResultsWe found a significant single nucleotide polymorphism-based genetic correlation between ADHD and BPD in the full and age-restricted samples (rGfull = .64, p = 3.13 × 10-14; rGrestricted = .71, p = 4.09 × 10-16). The meta-analysis between the full BPD sample identified two genome-wide significant (prs7089973 = 2.47 × 10-8; prs11756438 = 4.36 × 10-8) regions located on chromosomes 6 (CEP85L) and 10 (TAF9BP2). Restricting the analyses to BPD cases with an early onset yielded one genome-wide significant association (prs58502974 = 2.11 × 10-8) on chromosome 5 in the ADCY2 gene. Additional nominally significant regions identified contained known expression quantitative trait loci with putative functional consequences for NT5DC1, NT5DC2, and CACNB3 expression, whereas functional predictions implicated ABLIM1 as an allele-specific expressed gene in neuronal tissue.ConclusionsThe single nucleotide polymorphism-based genetic correlation between ADHD and BPD is substantial, significant, and consistent with the existence of genetic overlap between ADHD and BPD, with potential differential genetic mechanisms involved in early and later BPD onset.

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. © 2014 The Author(s).

Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P < 5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

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 OBJECTIVES: Evidence suggests the involvement of the dopamine D4 receptor gene (DRD4) in the pathogenesis of ADHD, but the exact mechanism is not well understood. Earlier reports on the effects of DRD4 polymorphisms on neurocognitive and neuroimaging measures are inconsistent. This study investigated the functional consequences of the 7-repeat allele of DRD4 on neurocognitive endophenotypes of ADHD in the Dutch subsample of the International Multicenter ADHD Genetics study. METHODS: Participants were 350 children (5-11.5 years) and adolescents (11.6-19 years) with ADHD and their 195 non-affected siblings. An overall measure of neuropsychological functioning was derived by principal component analysis from five neurocognitive and five motor tasks. The effects of DRD4 and age were examined using Linear Mixed Model analyses. RESULTS: The analyses were stratified for affected and non-affected participants after finding a significant three-way interaction between ADHD status, age and the 7-repeat allele. Apart from a main effect of age, a significant interaction effect of age and DRD4 was found in non-affected but not in affected participants, with non-affected adolescent carriers of the 7-repeat allele showing worse neuropsychological performance. In addition, carrying the 7-repeat allele of DRD4 was related to a significantly worse performance on verbal working memory in non-affected siblings, independent of age. CONCLUSIONS: These results might indicate that the effect of the DRD4 7-repeat allele on neuropsychological functioning is dependent on age and ADHD status.

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.

Research suggests that people adapt their own drinking behavior to that of others. Studies have shown that when being in the company of a heavy drinking peer, individuals tend to drink substantially more than when being with a non-drinking or light-drinking peer. However, not everyone is equally susceptible to other people’s drinking behavior. Based on genetic differences some individuals might be more inclined to adapt their own level of alcohol consumption to that of other people. In this study we used a 3 (drinking condition) by 2 (genotype) experimental design to test whether higher susceptibility to alcohol-related cues (i.e. seeing someone drink) was related to the DRD4 VNTR 7-repeat polymorphism (N = 113). A strong gene-environment interaction showed that participants carrying at least one copy of the 7-repeat allele consumed substantially more alcohol in the presence of heavy-drinking others than those without the risk allele. This study highlights that individual variability in sensitivity to other people’s drinking behavior may be attributed to genetic differences. Carrying the 7-repeat allele may increase the risk for heavy alcohol use when in the company of heavy-drinking peers.

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.

Contains fulltext : 167851.pdf (Publisher’s version ) (Open Access) BACKGROUND: Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection. METHODS: Children diagnosed with and/or treated for a structural birth defect or childhood cancer and their parents are invited to participate in the AGORA data- and biobank. Controls are recruited through random sampling from municipal registries. The parents receive questionnaires about demographics, family and pregnancy history, health status, prescribed medication, lifestyle, and occupational exposures before and during the index pregnancy. In addition, blood or saliva is collected from children and parents, while medical records are reviewed for diagnostic information. RESULTS: So far, we have collected data from over 6,860 families (3,747 birth defects, 905 childhood cancers, and 2,208 controls). The types of birth defects vary widely and comprise malformations of the digestive, respiratory, and urogenital tracts as well as facial, cardiovascular, kidney, skeletal, and central nervous system anomalies. The most frequently occurring childhood cancer types are acute lymphatic leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms' tumor, and brain and spinal cord tumors. Our genetic and/or epidemiologic studies have been focused on hypospadias, anorectal malformations, congenital anomalies of the kidney and urinary tract (CAKUT), and orofacial clefts. CONCLUSION: The large AGORA data- and biobank offers great opportunities for investigating genetic and nongenetic risk factors for disorders in children and is open to collaborative initiatives. Birth Defects Research (Part A) 106:675-684, 2016. (c) 2016 Wiley Periodicals, Inc.

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