Genetic and environmental components to self-induced vomiting

Objective We examined the association between the genetic and environmental factors contributing to the liability to having ever engaged in self-induced vomiting (SIV initiation) and the genetic and environmental factors contributing to regular SIV behaviors (weekly or daily) for weight control. Method SIV was assessed in 3,942 women from monozygotic twin pairs and 2,790 women from same-sex dizygotic twin pairs, aged 20-47, from the Swedish Twin study of Adults: Genes and Environment. A causal-contingent-common pathway model assessed the extent to which genetic and environmental factors that influence initiation of SIV also influence regular SIV behaviors. Results In the best-fit model, genetic and individual-specific environmental factors influenced liability to SIV initiation. The genetic factors influencing regular SIV behaviors were the same as the genetic factors influencing SIV initiation. Additional individual-specific environmental factors that were unrelated to SIV initiation influenced regular SIV behaviors. Discussion Our findings provide evidence that the underlying liabilities for SIV initiation and regular SIV lie on the same continuum given the degree of overlap in risk between SIV initiation and regular SIV behaviors. Further, the lack of specific genetic factors and the importance of individual-specific environmental factors for regular SIV behaviors highlight the significance of environmental factors in the etiology of eating disorder symptomatology and the non-deterministic nature of genetic factors. Finally, our results suggest that when it comes to preventing individuals from developing regular SIV behavior, intervening at an environmental level is warranted

Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway

During early brain development, N-methyl-d-aspartate (NMDA) receptors are involved in cell migration, neuritogenesis, axon guidance and synapse formation, but the mechanisms which regulate NMDA receptor density and function remain unclear. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at NMDA receptors and we have previously shown that inhibition of the pathway using the kynurenine-3-monoxygenase inhibitor Ro61-8048 in late gestation produces rapid changes in protein expression in the embryos and effects on synaptic transmission lasting until postnatal day 21 (P21). The present study sought to determine whether any of these effects are maintained into adulthood. After prenatal injections of Ro61-8048 the litter was allowed to develop to P60 when some offspring were euthanized and the brains removed for examination. Analysis of protein expression by Western blotting revealed significantly reduced expression of the GluN2A subunit (32%) and the morphogenetic protein sonic hedgehog (31%), with a 29% increase in the expression of doublecortin, a protein associated with neurogenesis. No changes were seen in mRNA abundance using quantitative real-time polymerase chain reaction. Neuronal excitability was normal in the CA1 region of hippocampal slices but paired-pulse stimulation revealed less inhibition at short interpulse intervals. The amount of long-term potentiation was decreased by 49% in treated pups and recovery after low-frequency stimulation was delayed. The results not only strengthen the view that basal, constitutive kynurenine metabolism is involved in normal brain development, but also show that changes induced prenatally can affect the brains of adult offspring and those changes are quite different from those seen previously at weaning (P21). Those changes may be mediated by altered expression of NMDAR subunits and sonic hedgehog

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

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)

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

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Aspirin and nonsteroidal anti‐inflammatory drug use and keratinocyte cancers: a large population‐based cohort study of skin cancer in Australia

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been postulated as chemopreventive agents for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), but findings from observational studies have been inconsistent, and clinical trial data are scant.To examine the association between aspirin and NSAID (nonaspirin) use and the risk of BCC and SCC in a large cohort specifically designed for skin cancer outcomes.We used data from the QSkin Study, a prospective cohort of 43\ua0764 residents of Queensland, Australia (34\ua0630 were included in this study and 23\ua0581 were used in our primary analyses). We used Cox proportional hazards models to estimate the hazard ratios (HRs) between self-reported aspirin and NSAID use 1 year prior to study baseline and the first histologically confirmed BCC or SCC for high-risk (history of skin cancer excisions or more than five actinic lesions treated) and average-to-low-risk participants (no history of skin cancer excision and at most five actinic lesions treated).After a median of 3 years of follow-up, 3421 participants developed BCC and 1470 SCC (2288 BCC and 932 SCC with complete covariate information). Among the high-risk group (1826 BCC and 796 SCC), compared with never use, frequent (at least weekly) NSAID use was associated with reduced risk of BCC (HR 0·84, 95% confidence interval 0·71-0.99) but not SCC. Aspirin use was associated with reduced risk of SCC (HR 0·77, 95% confidence interval 0·64-0·93) only among infrequent (less than weekly) users and was not associated with BCC. We observed no association between NSAID or aspirin use and the risk of BCC or SCC among average-to-low-risk participants.While some weakly inverse associations were observed between prior use of aspirin or NSAIDs and skin cancer, the inconsistent patterns of associations do not provide convincing evidence that these medications reduce subsequent skin cancer risk. Further data on doses, duration and long-term follow-up may help us to comprehend the cumulative dose effect

Combinaison de données multi-fréquence micro-ondes et optiques pour le suivi des cultures

[Departement_IRSTEA]GT [TR1_IRSTEA]GMA1-Fonctionnement hydrologique des bassins et des réseaux hydrographiquesInternational audienceThe potential for the combined use of microwave and optical data for farm management was explored based on images acquired in the visible, near-infrared, and thermal spectrum, and the synthetic aperture radar (SAR) wavelengths in the Ku (14.85 GHz) and C (5.3 GHz) bands. The images were obtained during June 1994, and covered an agricultural site composed of large fields of partial-cover cotton, near-full-cover alfalfa and bare soil fields of varying roughness. Results showed that the SAR Ku backscatter coefficient (Ku-band so) was sensitive to soil roughness and insensitive to soil moisture conditions when vegetation was present. When soil roughness conditions were relatively similar (e.g., for cotton fields of similar row direction and for all alfalfa fields), Ku-band so was sensitive to the fraction of the surface covered by vegetation. Under these conditions, the Ku-band so and the optical normalized difference vegetation index (NDVI) were generally correlated. The SAR C backscatter coefficient (C-band so) was found to be sensitive to soil moisture conditions for cotton fields with green leaf area index (GLAI) less than 1.0 and alfalfa fields with GLAI nearly 2.0. For both low-GLAI cotton and alfalfa, C-band so was correlated with measurements of surface temperature (Ts). A theoretical basis for the relations between Ku-band so and NDVI and between C-band so and Ts was presented, and supported with on-site measurements. Based on these findings, some combined optical/radar approaches were suggested for farm management applications.La possibilité de combiner des données de télédétection micro-ondes et optiques pour la suivi des cultures est étudié, en utilisant des images acquises dans le visible, le proche infrarouge, le thermique et dans les longueurs d'onde d'un SAR (radar à ouverture synthétique) dans les bandes Ku (14.85 GHz) et C (5.3 GHz). Les images ont été obtenues en juin 1994, et couvraient un site agricole composé de grandes parcelles de coton, luzerne et sol nu. Les résultats montrent que le coefficient de rétrodiffusion en bande Ku (Ku so) est sensible à la rugosité du sol et indépendant de l'humidité du sol en présence de végétation. Lorsque les conditions de rugosité du sol sont relativement similaires (p.ex. parcelles de coton dont les rangs sont orientés dans la même direction, parcelles de luzerne), Ku so est sensible au pourcentage de recouvrement de la végétation. Dans ces conditions, Ku so et l'indice de végétation NDVI sont en général corrélés. Le coefficient de rétrodiffusion en bande C (C so) est sensible aux conditions d'humidité du sol pour les parcelles de coton dont l'indice foliaire (GLAI) est inférieur à 1.0 et pour les parcelles de luzerne dont le GLAI est proche de 2 : dans les deux cas, C so est corrélé aux mesures de température de surface Ts. Une approche théorique des relations entre Ku so et NDVI, et entre C so et Ts est présentée, et validée par les mesures terrain. A partir de ces résultats, quelques approches combinant optique et radar sont proposées pour le suivi des cultures à l'échelle de l'exploitation