Independent mechanisms target SMCHD1 to trimethylated histone H3 lysine 9-modified chromatin and the inactive X chromosome

The chromosomal protein SMCHD1 plays an important role in epigenetic silencing at diverse loci, including the inactive X chromosome, imprinted genes, and the facioscapulohumeral muscular dystrophy locus. Although homology with canonical SMC family proteins suggests a role in chromosome organization, the mechanisms underlying SMCHD1 function and target site selection remain poorly understood. Here we show that SMCHD1 forms an active GHKL-ATPase homodimer, contrasting with canonical SMC complexes, which exist as tripartite ring structures. Electron microscopy analysis demonstrates that SMCHD1 homodimers structurally resemble prokaryotic condensins. We further show that the principal mechanism for chromatin loading of SMCHD1 involves an LRIF1-mediated interaction with HP1γ at trimethylated histone H3 lysine 9 (H3K9me3)-modified chromatin sites on the chromosome arms. A parallel pathway accounts for chromatin loading at a minority of sites, notably the inactive X chromosome. Together, our results provide key insights into SMCHD1 function and target site selection

The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.We thank members of the Cambridge BioResource Scientific Advisory Board and Management Committee for their support of our study and the National Institute for Health Research Cambridge Biomedical Research Centre for funding. K.D. is funded as a HSST trainee by NHS Health Education England. M.F. is funded from the BLUEPRINT Grant Code HEALTH-F5-2011-282510 and the BHF Cambridge Centre of Excellence [RE/13/6/30180]. J.R.S. is funded by a MRC CASE Industrial studentship, co-funded by Pfizer. J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health Research (NIHR) Senior Investigator. S.M., S.T, M.H, K.M. and L.D. are supported by the NIHR BioResource-Rare Diseases, which is funded by NIHR. Research in the Ouwehand laboratory is supported by program grants from the NIHR to W.H.O., the European Commission (HEALTH-F2-2012-279233), the British Heart Foundation (BHF) to W.J.A. and D.R. under numbers RP-PG-0310-1002 and RG/09/12/28096 and Bristol Myers-Squibb; the laboratory also receives funding from NHSBT. W.H.O is a NIHR Senior Investigator. The INTERVAL academic coordinating centre receives core support from the UK Medical Research Council (G0800270), the BHF (SP/09/002), the NIHR and Cambridge Biomedical Research Centre, as well as grants from the European Research Council (268834), the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), Merck and Pfizer. DJR and DA were supported by the NIHR Programme ‘Erythropoiesis in Health and Disease’ (Ref. NIHR-RP-PG-0310-1004). N.S. is supported by the Wellcome Trust (Grant Codes WT098051 and WT091310), the EU FP7 (EPIGENESYS Grant Code 257082 and BLUEPRINT Grant Code HEALTH-F5-2011-282510). The INTERVAL study is funded by NHSBT and has been supported by the NIHR-BTRU in Donor Health and Genomics at the University of Cambridge in partnership with NHSBT. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health of England or NHSBT. D.G. is supported by a “la Caixa”-Severo Ochoa pre-doctoral fellowship

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Missed Opportunities: Intimate Partner Violence in Family Practice Settings

Background. For women experiencing partner violence, women health care visits represent opportunities for physicians and patients to address intimate partner violence (IPV), a significant health threat for women. Objectives. The objectives were to estimate rates of physician documentation of IPV in medical records; characterize IPV+ women most likely to have IPV documented; and determine whether IPV screening increased IPV documentation. Methods. Subjects were women ages 18–65 receiving primary care in two large family practice clinics. All were screened for IPV by study staff using a modified Index of Spouse Abuse and the Women\u27s Experience with Battering scales. We selected and abstracted medical records for all women experiencing current IPV (N = 144) and a random sample of women never experiencing IPV (N = 147). Results. Of 144 women screened as currently experiencing IPV, 14.7% were documented. Women most likely to have IPV documented were Caucasian, with higher WEB scores, and more likely to have an event that could trigger posttraumatic stress syndrome. Although the majority (41/56) of women currently in physically violent relationships did not plan to disclose IPV, those disclosing were significantly more likely to have IPV documented and documentation occurred after screening for 60% of women experiencing IPV. Conclusion. IPV screening increased documentation. IPV screening can provide the opportunity for patients to disclose IPV. Physicians then have the opportunity to compassionately connect patients with appropriate resources

Physical and Mental Health Effects of Intimate Partner Violence for Men and Women

Background Few population-based studies have assessed the physical and mental health consequences of both psychological and physical intimate partner violence (IPV) among women or men victims. This study estimated IPV prevalence by type (physical, sexual, and psychological) and associated physical and mental health consequences among women and men. Methods The study analyzed data from the National Violence Against Women Survey (NVAWS) of women and men aged 18 to 65. This random-digit-dial telephone survey included questions about violent victimization and health status indicators. Results A total of 28.9% of 6790 women and 22.9% of 7122 men had experienced physical, sexual, or psychological IPV during their lifetime. Women were significantly more likely than men to experience physical or sexual IPV (relative risk [RR]=2.2, 95% confidence interval [CI]=2.1, 2.4) and abuse of power and control (RR=1.1, 95% CI=1.0, 1.2), but less likely than men to report verbal abuse alone (RR=0.8, 95% CI=0.7, 0.9). For both men and women, physical IPV victimization was associated with increased risk of current poor health; depressive symptoms; substance use; and developing a chronic disease, chronic mental illness, and injury. In general, abuse of power and control was more strongly associated with these health outcomes than was verbal abuse. When physical and psychological IPV scores were both included in logistic regression models, higher psychological IPV scores were more strongly associated with these health outcomes than were physical IPV scores. Conclusions Both physical and psychological IPV are associated with significant physical and mental health consequences for both male and female victims

Diversity and prevalence of hemoparasites of wading birds in southern Florida, USA

Relatively few studies on hemoparasites have been conducted on wading birds in the families Ardeidae and Threskiornithidae (order Pelecaniformes), especially in the United States. In this study, we obtained baseline data on the prevalence and genetic diversity of haemosporidian parasites in wading birds opportunistically sampled from southern Florida, USA. We detected blood parasites in White Ibis (Eudocimus albus), Glossy Ibis (Plegadis falcinellus), Green Heron (Butorides virescens), and Roseate Spoonbill (Platalea ajaja) with several novel host-parasite relationships. Infected birds had low parasitemias (average 0.77%, range 0–4%) suggesting that infections were chronic. Despite the low sample sizes for several of our sampled species, these data highlight the diversity of parasites in this understudied group of birds and suggest that additional studies are needed to investigate the potential impacts of these parasites on their health, especially since southern Florida is becoming increasingly urbanized which can alter parasite transmission or host susceptibility. Keywords: Avian malaria, Florida, Haemoproteus plataleae, haemosporidia, Pelicaniformes, Plasmodium, Wading birds, White Ibi

Prevention of sexual violence among college students: Current challenges and future directions

© 2020, © 2020 Taylor & Francis Group, LLC. Objective: Preventing sexual violence among college students is a public health priority. This paper was catalyzed by a summit convened in 2018 to review the state of the science on campus sexual violence prevention. We summarize key risk and vulnerability factors and campus-based interventions, and provide directions for future research pertaining to campus sexual violence. Results and Conclusions: Although studies have identified risk factors for campus sexual violence, longitudinal research is needed to examine time-varying risk factors across social ecological levels (individual, relationship, campus context/broader community and culture) and data are particularly needed to identify protective factors. In terms of prevention, promising individual and relational level interventions exist, including active bystander, resistance, and gender transformative approaches; however, further evidence-based interventions are needed, particularly at the community-level, with attention to vulnerability factors and inclusion for marginalized students