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Institute
The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
As part of a wider study of floodplain vegetation along the River Murray, we carried out a field survey in 1987–1988 involving collection of floristic and vegetation condition data from 335 sample plots (each 400 m2 in area), between Hume Dam and Lake Alexandrina (including the Edward-Wakool anabranch system). The floodplain vegetation is dominated by just two tree species, River Red Gum (Eucalyptus camaldulensis) and Black Box (Eucalyptus largiflorens), but the composition of the understorey shows much greater variation, both along the river and across the floodplain. A total of 499 plant species, subspecies and varieties were recorded from the survey plots, of which 316 (63%) were native and 183 (37%) were exotic. From analysis of the floristic data we identified 37 vegetation communities, not including the vegetation of permanent wetlands and cleared areas; 21 communities were distinguished in the River Red Gum zone, 12 communities in the Black Box zone, and 4 communities on rises within the floodplain. The main floristic division among the River Red Gum communities was between Riverine Plain/ Headwaters Zone communities of the upper Murray, and Mallee Zone communities of the lower Murray. Among the Black Box communities, the main floristic division was between inner floodplain communities and outer floodplain communities, with a further division between South Australian communities and New South Wales/Victorian communities. Major factors influencing the floristic patterns included flooding frequency/duration and soil salinity.
Eucalypt health declined steadily downstream and was poorest in the lower reaches of the river below the Darling Junction, where 60% of the trees were healthy, 18% unhealthy (at least 40% of the canopy dead) and 22% dead. By comparison, at the upper end of the river, above Tocumwal, 84% of the trees were healthy, 14% unhealthy and only 2% dead. Overall, the condition of Black Box trees (44% unhealthy or dead) was worse than the condition of River Red Gum trees (29% unhealthy or dead). Eucaypt regeneration was also poorest below the Darling Junction, with regenerants present in 77% of plots upstream of the Darling but only 35% of plots downstream. The findings of poor tree health and sparse regeneration below the Darling coincide with the most heavily regulated part of the Murray, where the reduction in flooding due to upstream storages and water extraction, mainly for irrigation, has been greatest. Black Box regeneration was much sparser overall than River Red Gum regeneration (regenerants present in 69% of River Red Gum plots but only 29% of Black Box plots). The poor condition of the Black Box trees, coupled with their poor regeneration, suggests that the long-term future of this species along the Murray, particularly below the Darling Junction, is tenuous, even though it is a dominant component of the vegetation.
The integrity of floodplain vegetation along the Murray has been severely compromised by weed invasion. Weeds were common throughout the survey area, but were most prevalent in the climatically wetter sections of the river, at both the downstream and upstream ends (below Mannum and above Tocumwal). The median number of exotic species per plot equalled or exceeded the number of native species in these sections of the river, whereas native species outnumbered exotic species in the other river sections. Communities of the River Red Gum zone and the rises were generally weedier than those of the Black Box zone. Exotic species strongly influenced the community classification. They were the dominant overstorey species in two communities (Salix species – willows) and outnumbered native species in the understorey of another eight communities. At the lower end of the river, below Mannum, the River Red Gums that originally fringed the river had been mostly replaced by dense thickets of the exotic Weeping Willow, Salix babylonica.
Other factors that have impacted on the floodplain vegetation at the plant community level have been river regulation and soil salinisation. Stabilization of water levels in the lower Murray by construction of a series of weirs and barrages has favoured the spread of some communities at the expense of others. The favoured communities, which are characterised by stands of Common Reed, Phragmites australis, along the water’s edge, appear to be artefacts of river regulation. Salinisation has resulted in death of eucalypts and replacement of eucalypt communities by shrub communities dominated by samphires, Tecticornia species. The samphire community characteristic of the most saline sites is one of the most species-poor communities on the Murray floodplain.
Logging along the Murray in New South Wales and Victoria has resulted in extensive replacement of old growth River Red Gum forests and woodlands by more even-aged stands of straight young trees. Following the recent conversion of many areas of State Forest along the Murray in both New South Wales and Victoria to National Park or Regional Park, and thus the cessation of logging in these areas, they should now revert gradually to mature forest and woodland.
This study is the first to describe broad scale floristic patterns in the floodplain vegetation of the Murray covering most of the length of the river. It also provides data on the vegetation condition in the 1980s, and provides a benchmark of conditions before the prolonged Millenium Drought in south-eastern Australia from 1997 to 2010. More recent surveys of vegetation condition have reported a severe decline in tree health during the drought. The results from our 1987–88 survey are important because they show that the deteriorating condition of the vegetation was already evident in the 1980s and although exacerbated by the subsequent drought, it is not just a consequence of that drought. The results are consistent with the conclusion that the primary cause of the decline has been river regulation and water extraction for irrigation. The rate of deterioration has increased rapidly since the 1980s because of the drought. There has been some improvement since the breaking of the drought, but the poor condition of the River Murray floodplain vegetation, an Australian icon, remains a major conservation and management issue. The impacts of climate change – higher temperatures and reduced rainfall – have compounded the problem and will continue to do so at an increasing rate. The results of the study support listing of the floodplain vegetation of the lower reaches of the river as a critically endangered ecological community.
The Greater Blue Mountains World Heritage Area (GBMWHA), a natural area of about one million hectares immediately west of Sydney, Australia, is significant for its biodiversity, and particularly for its richness of eucalypt species (species of Eucalyptus, Angophora and Corymbia in the family Myrtaceae), numbered at 96 species in 2010. This paper describes the finding of a previously unlisted Angophora species in the GBMWHA, and makes a conservation assessment of the population. A population of the Broad-leaved Apple Angophora subvelutina F. Muell. occurs at Euroka Clearing south of Glenbrook just within the eastern edge of Blue Mountains National Park, one of the eight conservation reserves that make up the GBMWHA. The population numbers over 200 plants and there is evidence that the species has been present at the site since before European settlement. The population includes a mixture of age classes and is considered viable, although substantial intergradation is occurring with the closely related species Angophora floribunda. Elsewhere in the Sydney area, the species is relatively uncommon and has been extensively cleared from its relatively fertile habitats. The population in the GBMWHA noted here has conservation significance for its size and long history at the site, and for the unusual ecological conditions of the Euroka diatreme, which is an atypical habitat for the species.
Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.
Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
Background: 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC.
Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 mug once weekly for 8 weeks, followed by s.c. L-BLP25 930 mug maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned.
Discussion: The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion. Trial Registration EudraCT Number 2011-000218-20