| 1. |
- Flannick, Jason, et al.
(author)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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In: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
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Journal article (peer-reviewed)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 2. |
- Fresard, Laure, et al.
(author)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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In: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Journal article (peer-reviewed)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 3. |
- Fuchsberger, Christian, et al.
(author)
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The genetic architecture of type 2 diabetes
- 2016
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
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Journal article (peer-reviewed)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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| 4. |
- Manning, Alisa, et al.
(author)
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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
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In: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
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Journal article (peer-reviewed)abstract
- To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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| 5. |
- Hawryluk, Gregory W. J., et al.
(author)
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A management algorithm for patients with intracranial pressure monitoring : the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC)
- 2019
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In: Intensive Care Medicine. - : Springer. - 0342-4642 .- 1432-1238. ; 45:12, s. 1783-1794
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Journal article (peer-reviewed)abstract
- Background: Management algorithms for adult severe traumatic brain injury (sTBI) were omitted in later editions of the Brain Trauma Foundation's sTBI Management Guidelines, as they were not evidence-based.Methods: We used a Delphi-method-based consensus approach to address management of sTBI patients undergoing intracranial pressure (ICP) monitoring. Forty-two experienced, clinically active sTBI specialists from six continents comprised the panel. Eight surveys iterated queries and comments. An in-person meeting included whole- and small-group discussions and blinded voting. Consensus required 80% agreement. We developed heatmaps based on a traffic-light model where panelists' decision tendencies were the focus of recommendations.Results: We provide comprehensive algorithms for ICP-monitor-based adult sTBI management. Consensus established 18 interventions as fundamental and ten treatments not to be used. We provide a three-tier algorithm for treating elevated ICP. Treatments within a tier are considered empirically equivalent. Higher tiers involve higher risk therapies. Tiers 1, 2, and 3 include 10, 4, and 3 interventions, respectively. We include inter-tier considerations, and recommendations for critical neuroworsening to assist the recognition and treatment of declining patients. Novel elements include guidance for autoregulation-based ICP treatment based on MAP Challenge results, and two heatmaps to guide (1) ICP-monitor removal and (2) consideration of sedation holidays for neurological examination.Conclusions: Our modern and comprehensive sTBI-management protocol is designed to assist clinicians managing sTBI patients monitored with ICP-monitors alone. Consensus-based (class III evidence), it provides management recommendations based on combined expert opinion. It reflects neither a standard-of-care nor a substitute for thoughtful individualized management.
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| 6. |
- Lang, Andrew S., et al.
(author)
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Assessing the Role of Seabirds in the Ecology of Influenza A Viruses
- 2016
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In: Avian diseases. - 0005-2086 .- 1938-4351. ; 60:1, s. 378-386
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Journal article (peer-reviewed)abstract
- Wild waterbirds, specifically waterfowl, gulls, and shorebirds, are recognized as the primordial reservoir of influenza A viruses (IAVs). However, the role of seabirds, an abundant, diverse, and globally distributed group of birds, in the perpetuation and transmission of IAVs is less clear. Here we summarize published and publicly available data for influenza viruses in seabirds, which for the purposes of this study are defined as birds that exhibit a largely or exclusively pelagic lifestyle and exclude waterfowl, gulls, and shorebirds, and we review this collective dataset to assess the role of seabirds in the influenza A ecology. Since 1961, more than 40,000 samples have been collected worldwide from the seabirds considered here and screened, using a variety of techniques, for evidence of active or past IAV infection. From these data, the overall prevalence of active infection has been estimated to be very low; however, serological data provide evidence that some seabird species are more frequently exposed to IAVs. Sequence data for viruses from seabirds are limited, except for murres (common murre, Uria aalge, and thick-billed murre, Uria lomvia; family Alcidae) for which there are full or partial genome sequences available for more than 80 viruses. Characterization of these viruses suggests that murres are infected with Group 1 hemagglutinin subtype viruses more frequently as compared to Group 2 and also indicates that these northern, circumpolar birds are frequently infected by intercontinental reassortant viruses. Greater temporal and spatial sampling and characterization of additional viruses are required to better understand the role of seabirds in global IAV dynamics.
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| 7. |
- Pauchard, Anibal, et al.
(author)
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Non-native and native organisms moving into high elevation and high latitude ecosystems in an era of climate change : new challenges for ecology and conservation
- 2016
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In: Biological Invasions. - : Springer Science and Business Media LLC. - 1387-3547 .- 1573-1464. ; 18:2, s. 345-353
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Journal article (peer-reviewed)abstract
- Cold environments at high elevation and high latitude are often viewed as resistant to biological invasions. However, climate warming, land use change and associated increased connectivity all increase the risk of biological invasions in these environments. Here we present a summary of the key discussions of the workshop 'Biosecurity in Mountains and Northern Ecosystems: Current Status and Future Challenges' (Flen, Sweden, 1-3 June 2015). The aims of the workshop were to (1) increase awareness about the growing importance of species expansion-both non-native and native-at high elevation and high latitude with climate change, (2) review existing knowledge about invasion risks in these areas, and (3) encourage more research on how species will move and interact in cold environments, the consequences for biodiversity, and animal and human health and wellbeing. The diversity of potential and actual invaders reported at the workshop and the likely interactions between them create major challenges for managers of cold environments. However, since these cold environments have experienced fewer invasions when compared with many warmer, more populated environments, prevention has a real chance of success, especially if it is coupled with prioritisation schemes for targeting invaders likely to have greatest impact. Communication and co-operation between cold environment regions will facilitate rapid response, and maximise the use of limited research and management resources.
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| 8. |
- Wille, Michelle, et al.
(author)
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A Pelagic Outbreak Of Avian Cholera In North American Gulls : Scavenging As A Primary Mechanism For Transmission?
- 2016
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In: Journal of Wildlife Diseases. - : Wildlife Disease Association. - 0090-3558 .- 1943-3700. ; 52:4, s. 793-802
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Journal article (peer-reviewed)abstract
- Avian cholera, caused by the bacterium Pasteurella multocida, is an endemic disease globally, often causing annual epizootics in North American wild bird populations with thousands of mortalities. From December 2006 to March 2007, an avian cholera outbreak caused mortality in marine birds off the coast of Atlantic Canada, largely centered 300-400 km off the coast of the island of Newfoundland. Scavenging gulls (Larus spp.) were the primary species detected; however, mortality was also identified in Black-legged Kittiwakes (Rissa tridactyla) and one Common Raven (Corvus corax), a nonmarine species. The most common gross necropsy findings in the birds with confirmed avian cholera were acute fibrinous and necrotizing lesions affecting the spleen, air sacs, and pericardium, and nonspecific hepatomegaly and splenomegaly. The etiologic agent, P. multocida serotype 1, was recovered from 77 of 136 carcasses examined, and confirmed or probable avian cholera was diagnosed in 85 cases. Mortality observed in scavenging gull species was disproportionately high relative to their abundance, particularly when compared to nonscavenging species. The presence of feather shafts in the ventricular lumen of the majority of larid carcasses diagnosed with avian cholera suggests scavenging of birds that died from avian cholera as a major mode of transmission. This documentation of an outbreak of avian cholera in a North American pelagic environment affecting primarily scavenging gulls indicates that offshore marine environments may be a component of avian cholera dynamics.
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