Substructures in lens galaxies: PG1115+080 and B1555+375, two fold configurations

We study the anomalous flux ratio which is observed in some four-image lens systems, where the source lies close to a fold caustic. In this case two of the images are close to the critical curve and their flux ratio should be equal to unity, instead in several cases the observed value differs significantly. The most plausible solution is to invoke the presence of substructures, as for instance predicted by the Cold Dark Matter scenario, located near the two images. In particular, we analyze the two fold lens systems PG1115+080 and B1555+375, for which there are not yet satisfactory models which explain the observed anomalous flux ratios. We add to a smooth lens model, which reproduces well the positions of the images but not the anomalous fluxes, one or two substructures described as singular isothermal spheres. For PG1115+080 we consider a smooth model with the influence of the group of galaxies described by a SIS and a substructure with mass $\sim 10^{5} M_{\odot}$ as well as a smooth model with an external shear and one substructure with mass $\sim 10^{8} M_{\odot}$ . For B1555+375 either a strong external shear or two substructures with mass $\sim 10^{7} M_{\odot}$ reproduce the data quite well.Comment: 26 pages, updated bibliography, Accepted for publication in Astrophysics & Space Scienc

Spatio-temporal genetic tagging of a cosmopolitan planktivorous shark provides insight to gene flow, temporal variation and site-specific re-encounters

Migratory movements in response to seasonal resources often influence population structure and dynamics. Yet in mobile marine predators, population genetic consequences of such repetitious behaviour remain inaccessible without comprehensive sampling strategies. Temporal genetic sampling of seasonally recurring aggregations of planktivorous basking sharks, Cetorhinus maximus, in the Northeast Atlantic (NEA) affords an opportunity to resolve individual re-encounters at key sites with population connectivity and patterns of relatedness. Genetic tagging (19 microsatellites) revealed 18% of re-sampled individuals in the NEA demonstrated inter/multi-annual site-specific re-encounters. High genetic connectivity and migration between aggregation sites indicate the Irish Sea as an important movement corridor, with a contemporary effective population estimate (Ne) of 382 (CI = 241–830). We contrast the prevailing view of high gene flow across oceanic regions with evidence of population structure within the NEA, with early-season sharks off southwest Ireland possibly representing genetically distinct migrants. Finally, we found basking sharks surfacing together in the NEA are on average more related than expected by chance, suggesting a genetic consequence of, or a potential mechanism maintaining, site-specific re-encounters. Long-term temporal genetic monitoring is paramount in determining future viability of cosmopolitan marine species, identifying genetic units for conservation management, and for understanding aggregation structure and dynamics

Vasculogenic properties of adventitial Sca-1(+)CD45(+) progenitor cells in mice: a potential source of vasa vasorum in atherosclerosis

The cellular origins of vasa vasorum are ill-defined and may involve circulating or local progenitor cells. We previously discovered that murine aortic adventitia contains Sca-1⁺CD45⁺ progenitors that produce macrophages. Here we investigated whether they are also vasculogenic. In aortas of C57BL/6 mice, Sca-1⁺CD45⁺ cells were localised to adventitia and lacked surface expression of endothelial markers (<1% for CD31, CD144, TIE-2). In contrast, they did show expression of CD31, CD144, TIE-2 and VEGFR2 in atherosclerotic ApoE(-/-) aortas. Although Sca-1⁺CD45⁺ cells from C57BL/6 aorta did not express CD31, they formed CD31⁺ colonies in endothelial differentiation media and produced interconnecting vascular-like cords in Matrigel that contained both endothelial cells and a small population of macrophages, which were located at branch points. Transfer of aortic Sca-1⁺CD45⁺ cells generated endothelial cells and neovessels de novo in a hindlimb model of ischaemia and resulted in a 50% increase in perfusion compared to cell-free control. Similarly, their injection into the carotid adventitia of ApoE(-/-) mice produced donor-derived adventitial and peri-adventitial microvessels after atherogenic diet, suggestive of newly formed vasa vasorum. These findings show that beyond its content of macrophage progenitors, adventitial Sca-1⁺CD45⁺ cells are also vasculogenic and may be a source of vasa vasorum during atherogenesis.Deborah Toledo-Flores, Anna Williamson, Nisha Schwarz, Sanuja Fernando, Catherine Dimasi, Tyra A. Witt, Thao M. Nguyen, Amrutesh S . Puranik, Colin D. Chue, Sinny Delacroix, Daniel B. Spoon, Claudine S. Bonder, Christina A. Bursill, Belinda A. Di Bartolo, Stephen J. Nicholls, Robert D. Simari, Peter J. Psalti

Relationships between Challenge Tour golfers’ clubhead velocity and force producing capabilities during a countermovement jump and isometric mid-thigh pull

A number of field-based investigations have evidenced practically significant relationships between clubhead velocity (CHV), vertical jump performance and maximum strength. Unfortunately, whilst these investigations provide a great deal of external validity, they are unable to ascertain vertical ground reaction force (vGRF) variables that may relate to golfers’ CHVs. This investigation aimed to assess if the variance in European Challenge Tour golfers’ CHVs could be predicted by countermovement jump (CMJ) positive impulse (PI), isometric mid-thigh pull (IMTP) peak force (PF) and rate of force development (RFD) from 0–50 ms, 0–100 ms, 0–150 ms and 0–200 ms. Thirty-one elite level European Challenge Tour golfers performed a CMJ and IMTP on dual force plates at a tournament venue, with CHV measured on a driving range. Hierarchical multiple regression results indicated that the variance in CHV was significantly predicted by all four models (model one R2 = 0.379; model two R2 = 0.392, model three R2 = 0.422, model four R2 = 0.480), with Akaike’s information criterion indicating that model one was the best fit. Individual standardised beta coefficients revealed that CMJ PI was the only significant variable, accounting for 37.9% of the variance in European Challenge Tour Golfers’ CHVs

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)

The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function

Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.Peer reviewe

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

Genome-wide by Environment Interaction Studies of Depressive Symptoms and Psychosocial Stress in UK Biobank and Generation Scotland

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 x 10(-6)). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 x 10(-9); total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 x 10(-8); dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 x 10(-8); dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 x 10(-6)). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 x 10(-3)). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions