Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Detectable clonal mosaicism and its relationship to aging and cancer

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases

Leveraging City Data to Understand the Opioid Epidemic in Philadelphia

ObjectiveTo match fatal overdose information across city data sources to understand which systems overdose decedents may have interacted with prior to their deathIntroductionPhiladelphia is in the midst of a drug epidemic that killed 702 Philadelphians in 2015, 907 in 2016, and is on trajectory to kill 1,200 in 2017. Opioids are involved in the majority of fatal overdoses, contributing to 80% of overdose deaths in 2016. In 2016, the age-adjusted death rate for opioid-involved overdoses was 40.4 deaths per 100,000 residents, up from 17.9 deaths per 100,000 residents in 2010. Despite the epidemiologic work accomplished to date, gaps in knowledge still exist, especially for vulnerable populations such as those with serious mental illness or those who were ever incarcerated, homeless, or within the juvenile justice system. Matching individuals who died of an overdose across city systems could provide insight into missed opportunities for interventions. Findings will help inform policy for those systems that serve clients at highest risk for overdose.MethodsIndividuals who succumbed to fatal overdoses involving opioids between January 1, 2012 and June 30, 2016 were matched to other city data systems going back to January 1, 2000. Descriptions of city systems that were matched to fatal overdose data is provided in Table 1. Frequencies were calculated to determine the number of individuals who received services or received services in the three years prior to death, as indicated by one of the city systems.ResultsBetween January 1, 2012 and June 30, 2016, 2,163 individuals died from an opioid-involved overdose. Overdose decedents were predominately male (69.1%), between the ages of 25-34 (28.0%), and white, non-Hispanic (63.5%). Heroin was the most common opioid detected in the system found in 67.1% of overdose decedents. In the years prior to death, 75.4% of individuals had received a service provided by a city agency and 61.6% had received a service within the three years immediately prior to death. Overdose decedents utilized the most services from Community Behavioral Health (CBH), a managed care organization providing behavioral health services for Philadelphia’s Medicaid population, both ever (59.5%) and in the three years prior to death (46.2%). Many decedents were also incarcerated within the Department of Prisons with 50.4% ever incarcerated and 27.9% incarcerated in the three years prior to death (Table 2). Additionally, 20.9% and 17.5% of overdose decedents had a positive STD or hepatitis C test, respectively, ever reported to the Department of Public Health (Table 3).ConclusionsThis match of overdose decedents to other city systems highlights missed opportunities to help individuals who struggle with opioid dependence. Historically, Philadelphia has taken a recovery oriented approach to drug use, which focuses on drug treatment, and these data suggest that this approach is not sufficient for preventing subsequent fatal overdose. A harm reduction approach, which seeks to reduce the harms of drug use through interventions such as overdose reversal training and naloxone distribution, needle and syringe exchange, and education on safe injection practices, needs to be prioritized in this epidemic alongside recovery oriented practices

Tilorone-Dihydrochloride Protects against Rift Valley Fever Virus Infection and Disease in the Mouse Model

Rift Valley fever (RVF) is a mosquito-borne zoonotic disease endemic to Africa and the Middle East that can affect humans and ruminant livestock. Currently, there are no approved vaccines or therapeutics for the treatment of severe RVF disease in humans. Tilorone-dihydrochloride (Tilorone) is a broad-spectrum antiviral candidate that has previously shown efficacy against a wide range of DNA and RNA viruses, and which is clinically utilized for the treatment of respiratory infections in Russia and other Eastern European countries. Here, we evaluated the antiviral activity of Tilorone against Rift Valley fever virus (RVFV). In vitro, Tilorone inhibited both vaccine (MP-12) and virulent (ZH501) strains of RVFV at low micromolar concentrations. In the mouse model, treatment with Tilorone significantly improved survival outcomes in BALB/c mice challenged with a lethal dose of RVFV ZH501. Treatment with 30 mg/kg/day resulted in 80% survival when administered immediately after infection. In post-exposure prophylaxis, Tilorone resulted in 30% survival at one day after infection when administered at 45 mg/kg/day. These findings demonstrate that Tilorone has potent antiviral efficacy against RVFV infection in vitro and in vivo and supports further development of Tilorone as a potential antiviral therapeutic for treatment of RVFV infection

Human neural stem cell-derived neuron/astrocyte co-cultures respond to La Crosse virus infection with proinflammatory cytokines and chemokines

Abstract Background La Crosse virus (LACV) causes pediatric encephalitis in the USA. LACV induces severe inflammation in the central nervous system, but the recruitment of inflammatory cells is poorly understood. A deeper understanding of LACV-induced neural pathology is needed in order to develop treatment options. However, there is a severe limitation of relevant human neuronal cell models of LACV infection. Methods We utilized human neural stem cell (hNSC)-derived neuron/astrocyte co-cultures to study LACV infection in disease-relevant primary cells. hNSCs were differentiated into neurons and astrocytes and infected with LACV. To characterize susceptibility and responses to infection, we measured viral titers and levels of viral RNA, performed immunofluorescence analysis to determine the cell types infected, performed apoptosis and cytotoxicity assays, and evaluated cellular responses to infection using qRT-PCR and Bioplex assays. Results hNSC-derived neuron/astrocyte co-cultures were susceptible to LACV infection and displayed apoptotic responses as reported in previous in vitro and in vivo studies. Neurons and astrocytes are both targets of LACV infection, with neurons becoming the predominant target later in infection possibly due to astrocytic responses to IFN. Additionally, neuron/astrocyte co-cultures responded to LACV infection with strong proinflammatory cytokine, chemokine, as well as MMP-2, MMP-7, and TIMP-1 responses. Conclusions hNSC-derived neuron/astrocyte co-cultures reproduce key aspects of LACV infection in humans and mice and are useful models to study encephalitic viruses. Specifically, we show astrocytes to be susceptible to LACV infection and that neurons and astrocytes are important drivers of the inflammatory responses seen in LACV infection through the production of proinflammatory cytokines and chemokines

Endothelial activation of caspase-9 promotes neurovascular injury in retinal vein occlusion

Retinal vein occlusion can cause blindness, and features neuronal dysfunction, inflammation and breakdown of vascular integrity. Here the authors report a non-apoptotic role of endothelial caspase-9 in regulating blood-retina barrier integrity and neuronal survival, which can be therapeutically targeted in a mouse model of retinal vein occlusion

Author Correction: Endothelial activation of caspase-9 promotes neurovascular injury in retinal vein occlusion

An amendment to this paper has been published and can be accessed via a link at the top of the paper