PARP1 gene variation and microglial activity on [11C]PBR28 PET in older adults at risk for Alzheimer's disease

Increasing evidence suggests that inflammation is one pathophysio-logical mechanism in Alzheimer's disease (AD). Recent studies have identified an association between the poly (ADP-ribose) polymerase 1 (PARP1) gene and AD. This gene encodes a protein that is involved in many biological functions, including DNA repair and chromatin remodeling, and is a mediator of inflammation. Therefore, we performed a targeted genetic association analysis to investigate the relationship between the PARP1 polymorphisms and brain micro-glial activity as indexed by [11C]PBR28 positron emission tomography (PET). Participants were 26 non-Hispanic Caucasians in the Indiana Memory and Aging Study (IMAS). PET data were intensity-normalized by injected dose/total body weight. Average PBR standardized uptake values (SUV) from 6 bilateral regions of interest (thalamus, frontal, parietal, temporal, and cingulate cortices, and whole brain gray matter) were used as endophenotypes. Single nucleotide polymorphisms (SNPs) with 20% minor allele frequency that were within +/− 20 kb of the PARP1 gene were included in the analyses. Gene-level association analyses were performed using a dominant genetic model with translocator protein (18-kDa) (TSPO) genotype, age at PET scan, and gender as covariates. Analyses were performed with and without APOE ε4 status as a covariate. Associations with PBR SUVs from thalamus and cingulate were significant at corrected p<0.014 and <0.065, respectively. Subsequent multi-marker analysis with cingulate PBR SUV showed that individuals with the “C” allele at rs6677172 and “A” allele at rs61835377 had higher PBR SUV than individuals without these alleles (corrected P<0.03), and individuals with the “G” allele at rs6677172 and “G” allele at rs61835377 displayed the opposite trend (corrected P<0.065). A previous study with the same cohort showed an inverse relationship between PBR SUV and brain atrophy at a follow-up visit, suggesting possible protective effect of microglial activity against cortical atrophy. Interestingly, all 6 AD and 2 of 3 LMCI participants in the current analysis had one or more copies of the “GG” allele combination, associated with lower cingulate PBR SUV, suggesting that this gene variant warrants further investigation

Working time flexibility components and working time regimes in Europe: using company-level data across 21 countries

Working time ?exibility comprises a wide variety of arrangements, from part-time, overtime, to long-term leaves. Theoretical approaches to grouping these arrangements have been developed, but empirical underpinnings are rare. This article investigates the bundles that can be found for various ?exible working time arrangements, using the Establishment Survey on Working Time and Work–Life Balance, 2004/2005, covering 21 EU member states and 13 industries. The results from the factor analyses con?rmed that working time arrangements can be grouped into two bundles, one for the employee-centred arrangements and second for the employer-centred arrangements, and that these two bundles are separate dimensions.Wealso tested the stability of the factor analysisoutcome, showing that although we ?nd some deviations from the pan-Europe and pan-industry outcome, the naming of the components as ?exibility for employees and ?exibility for employers can be considered rather stable. Lastly, we ?nd three country clusters for the 21 European countries using the bundle approach. The ?rst group includes the Northern European countries along side Poland and Czech Republic, the second group the continental European countries with UK and Ireland, and lastly, the southern European countries with Hungary and Slovenia

The Early Psychosis Screener for Internet (EPSI)-SR: Predicting 12 month psychotic conversion using machine learning

Introduction: A faster and more accurate self-report screener for early psychosis is needed to promote early identification and intervention. Methods: Self-report Likert-scale survey items were administered to individuals being screened with the Structured Interview for Psychosis-risk Syndromes (SIPS) and followed at eight early psychosis clinics. An a priori analytic plan included Spectral Clustering Analysis to reduce the item pool, followed by development of Support Vector Machine (SVM) classifiers. Results: The cross-validated positive predictive value (PPV) of the EPSI at the default cut-off (76.5%) exceeded that of the clinician-administered SIPS (68.5%) at separating individuals who would not convert to psychosis within 12 months from those who either would convert within 12 months or who had already experienced a first episode psychosis (FEP). When used in tandem with the SIPS on clinical high risk participants, the EPSI increased the combined PPV to 86.6%. The SVM classified as FEP/converters only 1% of individuals in non-clinical and 4% of clinical low risk populations. Sensitivity of the EPSI, however, was 51% at the default cut-off. Discussion: The EPSI identifies, comparably to the SIPS but in less time and with fewer resources, individuals who are either at very high risk to develop a psychotic disorder within 12 months or who are already psychotic. At its default cut-off, EPSI misses 49% of current or future psychotic cases. The cut-off can, however, be adjusted based on purpose. The EPSI is the first validated assessment to predict 12-month psychotic conversion. An online screening system, www.eps.telesage.org, is under development

Characterization of Single Gene Copy Number Variants in Schizophrenia

Background: Genetic studies of schizophrenia have implicated numerous risk loci including several copy number variants (CNVs) of large effect and hundreds of loci of small effect. In only a few cases has a specific gene been clearly identified. Rare CNVs affecting a single gene offer a potential avenue to discovering schizophrenia risk genes. Methods: CNVs were generated from exome sequencing of 4913 schizophrenia cases and 6188 control subjects from Sweden. We integrated two CNV calling methods (XHMM and ExomeDepth) to expand our set of single-gene CNVs and leveraged two different approaches for validating these variants (quantitative polymerase chain reaction and NanoString). Results: We found a significant excess of all rare CNVs (deletions: p = .0004, duplications: p = .0006) and single-gene CNVs (deletions: p = .04, duplications: p = .03) in schizophrenia cases compared with control subjects. An expanded set of CNVs generated from integrating multiple approaches showed a significant burden of deletions in 11 of 21 gene sets previously implicated in schizophrenia and across all genes in those sets (p = .008), although no tests survived correction. We performed an extensive validation of all deletions in the significant set of voltage-gated calcium channels among CNVs called from both exome sequencing and genotyping arrays. In total, 4 exonic, single-gene deletions were validated in schizophrenia cases and none in control subjects (p = .039), of which all were identified by exome sequencing. Conclusions: These results point to the potential contribution of single-gene CNVs to schizophrenia, indicate that the utility of exome sequencing for CNV calling has yet to be maximized, and note that single-gene CNVs should be included in gene-focused studies using other classes of variation

Motor-Driven Bacterial Flagella and Buckling Instabilities

Many types of bacteria swim by rotating a bundle of helical filaments also called flagella. Each filament is driven by a rotary motor and a very flexible hook transmits the motor torque to the filament. We model it by discretizing Kirchhoff's elastic-rod theory and develop a coarse-grained approach for driving the helical filament by a motor torque. A rotating flagellum generates a thrust force, which pushes the cell body forward and which increases with the motor torque. We fix the rotating flagellum in space and show that it buckles under the thrust force at a critical motor torque. Buckling becomes visible as a supercritical Hopf bifurcation in the thrust force. A second buckling transition occurs at an even higher motor torque. We attach the flagellum to a spherical cell body and also observe the first buckling transition during locomotion. By changing the size of the cell body, we vary the necessary thrust force and thereby obtain a characteristic relation between the critical thrust force and motor torque. We present a sophisticated analytical model for the buckling transition based on a helical rod which quantitatively reproduces the critical force-torque relation. Real values for motor torque, cell body size, and the geometry of the helical filament suggest that buckling should occur in single bacterial flagella. We also find that the orientation of pulling flagella along the driving torque is not stable and comment on the biological relevance for marine bacteria.Comment: 15 pages, 11 figure

Rotational propulsion enabled by inertia

The fluid mechanics of small-scale locomotion has recently attracted considerable attention, due to its importance in cell motility and the design of artificial micro-swimmers for biomedical applications. Most studies on the topic consider the ideal limit of zero Reynolds number. In this paper, we investigate a simple propulsion mechanism --an up-down asymmetric dumbbell rotating about its axis of symmetry-- unable to propel in the absence of inertia in a Newtonian fluid. Inertial forces lead to continuous propulsion for all finite values of the Reynolds number. We study computationally its propulsive characteristics as well as analytically in the small-Reynolds-number limit. We also derive the optimal dumbbell geometry. The direction of propulsion enabled by inertia is opposite to that induced by viscoelasticity

Improving Genetic Prediction by Leveraging Genetic Correlations Among Human Diseases and Traits

Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7 for height to 47 for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait. © 2018 The Author(s)

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu).Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1x10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p < 5x10-8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe