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- van Rheenen, W, et al.
(author)
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Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
- 2021
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 53:12, s. 1636-
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Journal article (peer-reviewed)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
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- Manzoni, Claudia, et al.
(author)
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Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia
- 2024
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In: American Journal of Human Genetics. - 0002-9297. ; 111:7, s. 1316-1329
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Journal article (peer-reviewed)abstract
- Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
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- Režen, T., et al.
(author)
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Expression changes in human skeletal muscle miRNAs following 10 days of bed rest in young healthy males
- 2014
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In: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 210:3, s. 655-666
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Journal article (peer-reviewed)abstract
- Aim: Studies in humans show global changes in mRNA and protein expression occur in human skeletal muscle during bed rest. As microRNAs are important regulators of expression, we analysed the global microRNA expression changes in human muscle following 10 days of sustained bed rest, with the rationale that miRNAs play key roles in atrophy of skeletal muscle. Methods: We analysed expression of miRNA and selected target proteins before and after 10 days of bed rest in biopsies obtained from the vastus lateralis muscle of 6 healthy males. Results: Fifteen of 152 miRNAs detected in human muscle tissue were differentially expressed, and all of them with exception of two were downregulated. The downregulated miRNAs include the following: miR-206, a myomir involved in function and maintenance of skeletal muscle; miR-23a, involved in insulin response and atrophy defence; and several members of the let-7 family involved in cell cycle, cell differentiation and glucose homeostasis. Predicted gene targets of these miRNAs are members of the MAPK, TNF receptor, ALK1, TGF-beta receptor and SMAD signalling pathways. All of these pathways were previously indicated to be involved in skeletal muscle response to physical inactivity. We also measured protein expression of selected miRNA targets and observed a decrease in HDAC4. Conclusion: Our data demonstrate that miRNAs in postural muscles are affected by sustained inactivity and unloading, as induced by prolonged bed rest, and hence are potentially involved in regulation of skeletal muscle adjustments to inactivity. We also propose new miRNAs involved in regulation of biological processes in adult human muscle.
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- Martin, Maria A., et al.
(author)
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Ten new insights in climate science 2021 : a horizon scan
- 2021
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In: Global Sustainability. - : Cambridge University Press (CUP). - 2059-4798. ; 4, s. 1-20
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Research review (peer-reviewed)abstract
- Non-technical summary: We summarize some of the past year's most important findings within climate change-related research. New research has improved our understanding about the remaining options to achieve the Paris Agreement goals, through overcoming political barriers to carbon pricing, taking into account non-CO2 factors, a well-designed implementation of demand-side and nature-based solutions, resilience building of ecosystems and the recognition that climate change mitigation costs can be justified by benefits to the health of humans and nature alone. We consider new insights about what to expect if we fail to include a new dimension of fire extremes and the prospect of cascading climate tipping elements.Technical summary: A synthesis is made of 10 topics within climate research, where there have been significant advances since January 2020. The insights are based on input from an international open call with broad disciplinary scope. Findings include: (1) the options to still keep global warming below 1.5 °C; (2) the impact of non-CO2 factors in global warming; (3) a new dimension of fire extremes forced by climate change; (4) the increasing pressure on interconnected climate tipping elements; (5) the dimensions of climate justice; (6) political challenges impeding the effectiveness of carbon pricing; (7) demand-side solutions as vehicles of climate mitigation; (8) the potentials and caveats of nature-based solutions; (9) how building resilience of marine ecosystems is possible; and (10) that the costs of climate change mitigation policies can be more than justified by the benefits to the health of humans and nature.Social media summary: How do we limit global warming to 1.5 °C and why is it crucial? See highlights of latest climate science.
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- Mekjavic, Igor B., et al.
(author)
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Inhalation of warm and cold air does not influence brain stem or core temperature in normothermic humans
- 2002
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In: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 93:1, s. 65-69
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Journal article (peer-reviewed)abstract
- The present study tested the hypothesis that inhalation rewarming provides a thermal increment to central neural structures adjacent to the nasopharyngeal region. Auditory-evoked brain stem responses of 14 subjects (7 men and 7 women) were monitored for 25 min while they inspired room air (24 degrees C) followed by hot air (41 degrees C) saturated with water vapor and cold dry air (-1 degrees C). The latencies of peaks I, III, and V and the interpeak latencies (IPLs) I-III, III-V, and I-V were compared among the three conditions with a repeated-measures ANOVA. Changes in IPLs are sensitive markers of changes in brain stem temperature. Tympanic temperature (T(ty)) was measured with an infrared tympanic thermometer. There were no significant differences in T(ty), peak latencies I, III, and V, and IPLs I-III, III-V, and I-V. The results indicate that inhalation of hot and cold air does not influence T(ty), nor does it influence the temperature of the brain stem. We conclude that inhalation rewarming is not capable of warming the vital central neural structures adjacent to the naropharynx.
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- Rogelj, Joeri, et al.
(author)
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Mitigation pathways compatible with 1.5°C in the context of sustainable development
- 2018
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In: Global Warming of 1.5°C. An IPCC Special Report on the impacts of global warming of 1.5°C above pre-industrial levels and related global greenhouse gas emission pathways, in the context of strengthening the global response to the threat of climate change, sustainable development, and efforts to eradicate poverty. ; , s. 93-174
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Book chapter (peer-reviewed)
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- Smith, Bradley N., et al.
(author)
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The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder
- 2013
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In: European Journal of Human Genetics. - London : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 21:1, s. 102-108
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Journal article (peer-reviewed)abstract
- A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n = 1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n = 434) and controls (n = 856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.
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- van Rheenen, Wouter, et al.
(author)
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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
- 2016
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
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Journal article (peer-reviewed)abstract
- To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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