| 1. |
- Månberg, Anna, 1985-, et al.
(author)
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Altered perivascular fibroblast activity precedes ALS disease onset
- 2021
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In: Nature Medicine. - : Nature Publishing Group. - 1078-8956 .- 1546-170X. ; 27:4, s. 640-646
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Journal article (peer-reviewed)abstract
- Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.
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| 2. |
- Naumann, Marcel, et al.
(author)
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Phenotypes and malignancy risk of different FUS mutations in genetic amyotrophic lateral sclerosis
- 2019
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In: Annals of Clinical and Translational Neurology. - : John Wiley & Sons. - 2328-9503. ; 6:12, s. 2384-2394
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Journal article (peer-reviewed)abstract
- Objective: Mutations in Fused in Sarcoma (FUS or TLS) are the fourth most prevalent in Western European familial amyotrophic lateral sclerosis (ALS) populations and have been associated with causing both early and very late disease onset. FUS aggregation, DNA repair deficiency, and genomic instability are contributors to the pathophysiology of FUS-ALS, but their clinical significance per se and their influence on the clinical variability have yet to be sufficiently investigated. The aim of this study was to analyze genotype-phenotype correlations and malignancy rates in a newly compiled FUS-ALS cohort.Methods: We cross-sectionally reviewed FUS-ALS patient histories in a multicenter cohort with 36 novel cases and did a meta-analysis of published FUS-ALS cases reporting the largest genotype-phenotype correlation of FUS-ALS.Results: The age of onset (median 39 years, range 11-80) was positively correlated with the disease duration. C-terminal domain mutations were found in 90%. Among all, P525L and truncating/ frameshift mutations most frequently caused juvenile onset, rapid disease progression, and atypical ALS often associated with negative family history while the R521 mutation site was associated with late disease onset and pure spinal phenotype. Malignancies were found in one of 40 patients.Interpretation: We report the largest genotype-phenotype correlation of FUS-ALS, which enables a careful prediction of the clinical course in newly diagnosed patients. In this cohort, FUS-ALS patients did not have an increased risk for malignant diseases.
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| 3. |
- Salonen, J. Sakari, et al.
(author)
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Abrupt high-latitude climate events and decoupled seasonal trends during the Eemian
- 2018
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- The Eemian (the Last Interglacial; ca. 129-116 thousand years ago) presents a testbed for assessing environmental responses and climate feedbacks under warmer-than-present boundary conditions. However, climate syntheses for the Eemian remain hampered by lack of data from the high-latitude land areas, masking the climate response and feedbacks in the Arctic. Here we present a high-resolution (sub-centennial) record of Eemian palaeoclimate from northern Finland, with multi-model reconstructions for July and January air temperature. In contrast with the mid-latitudes of Europe, our data show decoupled seasonal trends with falling July and rising January temperatures over the Eemian, due to orbital and oceanic forcings. This leads to an oceanic Late-Eemian climate, consistent with an earlier hypothesis of glacial inception in Europe. The interglacial is further intersected by two strong cooling and drying events. These abrupt events parallel shifts in marine proxy data, linked to disturbances in the North Atlantic oceanic circulation regime.
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| 4. |
- Salonen, J. Sakari, et al.
(author)
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Uncovering Holocene climate fluctuations and ancient conifer populations : Insights from a high-resolution multi-proxy record from Northern Finland
- 2024
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In: Global and Planetary Change. - 0921-8181 .- 1872-6364. ; 237
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Journal article (peer-reviewed)abstract
- A series of abrupt climate events linked to circum-North Atlantic meltwater forcing have been recognised in Holocene paleoclimate data. To address the paucity of proxy records able to characterise robustly the regional impacts of these events, we retrieved a sub-centennial resolution, well-dated core sequence from Lake Kuutsjarvi, northeast Finland. By analysing a range of paleo-environmental proxies (pollen, plant sedimentary ancient DNA, plant macrofossils, conifer stomata, and non-pollen palynomorphs), and supported with proxy-based paleotemperature and moisture reconstructions, we unravel a well-defined sequence of vegetation and climate dynamics over the early-to-middle Holocene. The birch-dominated pioneer vegetation stage was intersected by two transient tree-cover decrease events at 10.4 and 10.1 thousand years ago (ka), likely representing a two-pronged signal of the 10.3 ka climate event. Our data also show a clear signal of the 8.2 ka climate event, previously not well recorded in the European Arctic, with a collapse of the pine-birch forest and replacement by juniper developing in tight synchrony with Greenland isotopic proxies over 8.4-8.0 ka. Supported by climate modelling, severe winter cooling rather than summer might have been driving vegetation disruptions in the early Holocene. The Kuutsjarvi data indicate an early arrival of Norway spruce (Picea abies) by 9.2 ka (pollen, DNA, and stoma finds), as well as the first evidence for Holocene presence of larch (Larix) in Finland, with pollen finds dating to 9.6-5.9 ka.
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| 5. |
- Tazelaar, Gijs H. P., et al.
(author)
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Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort
- 2019
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In: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 74, s. 234.e9-234.e15
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Journal article (peer-reviewed)abstract
- NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with amyotrophic lateral sclerosis (ALS). Previously, a genomewide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to perform a large-scale replication study to further investigate the role of NIPA1 polyalanine expansions with ALS, in which we characterized NIPA1 repeat size in an independent international cohort of 3955 patients with ALS and 2276 unaffected controls and combined our results with previous reports. Meta-analysis on a total of 6245 patients with ALS and 5051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG repeat length (odds ratio = 1.50, p = 3.8×10−5). Together with previous reports, these findings provide evidence for an association of an expanded polyalanine repeat in NIPA1 and ALS.
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| 6. |
- Watson, Hunna J., et al.
(author)
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Common Genetic Variation and Age of Onset of Anorexia Nervosa
- 2022
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In: BIOLOGICAL PSYCHIATRY: GLOBAL OPEN SCIENCE. - : Elsevier BV. - 2667-1743. ; 2:4, s. 368-378
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Journal article (peer-reviewed)abstract
- BACKGROUND: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.METHODS: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (,13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.RESULTS: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early-and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early -onset AN.CONCLUSIONS: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.
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