| 1. |
- Ibanez, L., et al.
(författare)
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Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke
- 2022
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 145:7, s. 2394-2406
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Tidskriftsartikel (refereegranskat)abstract
- During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. Ibanez et al. perform a multi-ancestry meta-analysis to investigate the genetic architecture of early stroke outcomes. Two of the eight genome-wide significant loci identified-ADAM23 and GRIA1-are involved in synaptic excitability, suggesting that excitotoxicity contributes to neurological instability after ischaemic stroke.
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| 2. |
- Kostka, Kristin, et al.
(författare)
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Unraveling COVID-19: A Large-Scale Characterization of 4.5 Million COVID-19 Cases Using CHARYBDIS.
- 2022
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Ingår i: Clinical epidemiology. - 1179-1349. ; 14, s. 369-384
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Tidskriftsartikel (refereegranskat)abstract
- Routinely collected real world data (RWD) have great utility in aiding the novel coronavirus disease (COVID-19) pandemic response. Here we present the international Observational Health Data Sciences and Informatics (OHDSI) Characterizing Health Associated Risks and Your Baseline Disease In SARS-COV-2 (CHARYBDIS) framework for standardisation and analysis of COVID-19 RWD.We conducted a descriptive retrospective database study using a federated network of data partners in the United States, Europe (the Netherlands, Spain, the UK, Germany, France and Italy) and Asia (South Korea and China). The study protocol and analytical package were released on 11th June 2020 and are iteratively updated via GitHub. We identified three non-mutually exclusive cohorts of 4,537,153 individuals with a clinical COVID-19 diagnosis or positive test, 886,193 hospitalized with COVID-19, and 113,627 hospitalized with COVID-19 requiring intensive services.We aggregated over 22,000 unique characteristics describing patients with COVID-19. All comorbidities, symptoms, medications, and outcomes are described by cohort in aggregate counts and are readily available online. Globally, we observed similarities in the USA and Europe: more women diagnosed than men but more men hospitalized than women, most diagnosed cases between 25 and 60 years of age versus most hospitalized cases between 60 and 80 years of age. South Korea differed with more women than men hospitalized. Common comorbidities included type 2 diabetes, hypertension, chronic kidney disease and heart disease. Common presenting symptoms were dyspnea, cough and fever. Symptom data availability was more common in hospitalized cohorts than diagnosed.We constructed a global, multi-centre view to describe trends in COVID-19 progression, management and evolution over time. By characterising baseline variability in patients and geography, our work provides critical context that may otherwise be misconstrued as data quality issues. This is important as we perform studies on adverse events of special interest in COVID-19 vaccine surveillance.
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| 3. |
- Lane, Jennifer C E, et al.
(författare)
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Risk of depression, suicide and psychosis with hydroxychloroquine treatment for rheumatoid arthritis: a multinational network cohort study.
- 2021
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 60:7, s. 3222-3234
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Tidskriftsartikel (refereegranskat)abstract
- Concern has been raised in the rheumatology community regarding recent regulatory warnings that HCQ used in the coronavirus disease 2019 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation or psychosis associated with HCQ as used for RA.We performed a new-user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and USA). RA patients ≥18years of age and initiating HCQ were compared with those initiating SSZ (active comparator) and followed up in the short (30days) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HRs), with estimates pooled where I2<40%.A total of 918144 and 290383 users of HCQ and SSZ, respectively, were included. No consistent risk of psychiatric events was observed with short-term HCQ (compared with SSZ) use, with meta-analytic HRs of 0.96 (95% CI 0.79, 1.16) for depression, 0.94 (95% CI 0.49, 1.77) for suicide/suicidal ideation and 1.03 (95% CI 0.66, 1.60) for psychosis. No consistent long-term risk was seen, with meta-analytic HRs of 0.94 (95% CI 0.71, 1.26) for depression, 0.77 (95% CI 0.56, 1.07) for suicide/suicidal ideation and 0.99 (95% CI 0.72, 1.35) for psychosis.HCQ as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation or psychosis compared with SSZ. No effects were seen in the short or long term. Use at a higher dose or for different indications needs further investigation.Registered with EU PAS (reference no. EUPAS34497; http://www.encepp.eu/encepp/viewResource.htm? id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine2.
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| 4. |
- Abalde, Samuel, et al.
(författare)
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Hidden species diversity and mito-nuclear discordance within the Mediterranean cone snail, Lautoconus ventricosus
- 2023
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Ingår i: Molecular Phylogenetics and Evolution. - 1055-7903 .- 1095-9513. ; 186, s. 107838-107838
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Tidskriftsartikel (refereegranskat)abstract
- The Mediterranean cone snail, Lautoconus ventricosus, is currently considered a single species inhabiting the whole Mediterranean basin and the adjacent Atlantic coasts. Yet, no population genetic study has assessed its taxonomic status. Here, we collected 245 individuals from 75 localities throughout the Mediterranean Sea and used cox1 barcodes, complete mitochondrial genomes, and genome skims to test whether L. ventricosus represents a complex of cryptic species. The maximum likelihood phylogeny based on complete mitochondrial genomes recovered six main clades (hereby named blue, brown, green, orange, red, and violet) with sufficient sequence divergence to be considered putative species. On the other hand, phylogenomic analyses based on 437 nuclear genes only recovered four out of the six clades: blue and orange clades were thoroughly mixed and the brown one was not recovered. This mito-nuclear discordance revealed instances of incomplete lineage sorting and introgression, and may have caused important differences in the dating of main cladogenetic events. Species delimitation tests proposed the existence of at least three species: green, violet, and red + blue + orange (i.e., cyan). Green plus cyan (with sympatric distributions) and violet, had West and East Mediterranean distributions, respectively, mostly separated by the Siculo-Tunisian biogeographical barrier. Morphometric analyses of the shell using species hypotheses as factor and shell length as covariate showed that the discrimination power of the studied parameters was only 70.2%, reinforcing the cryptic nature of the uncovered species, and the importance of integrative taxonomic approaches considering morphology, ecology, biogeography, and mitochondrial and nuclear population genetic variation.
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| 5. |
- Irisarri, Iker, 1984-, et al.
(författare)
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A mitogenomic phylogeny of chitons (Mollusca: Polyplacophora)
- 2020
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Ingår i: BMC Evolutionary Biology. - : Springer Science and Business Media LLC. - 1471-2148. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPolyplacophora, or chitons, have long fascinated malacologists for their distinct and rather conserved morphology and lifestyle compared to other mollusk classes. However, key aspects of their phylogeny and evolution remain unclear due to the few morphological, molecular, or combined phylogenetic analyses, particularly those addressing the relationships among the major chiton lineages.ResultsHere, we present a mitogenomic phylogeny of chitons based on 13 newly sequenced mitochondrial genomes along with eight available ones and RNAseq-derived mitochondrial sequences from four additional species. Reconstructed phylogenies largely agreed with the latest advances in chiton systematics and integrative taxonomy but we identified some conflicts that call for taxonomic revisions. Despite an overall conserved gene order in chiton mitogenomes, we described three new rearrangements that might have taxonomic utility and reconstructed the most likely scenario of gene order change in this group. Our phylogeny was time-calibrated using various fossils and relaxed molecular clocks, and the robustness of these analyses was assessed with several sensitivity analyses. The inferred ages largely agreed with previous molecular clock estimates and the fossil record, but we also noted that the ambiguities inherent to the chiton fossil record might confound molecular clock analyses.ConclusionsIn light of the reconstructed time-calibrated framework, we discuss the evolution of key morphological features and call for a continued effort towards clarifying the phylogeny and evolution of chitons.
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| 6. |
- Uribe, Juan E., et al.
(författare)
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New patellogastropod mitogenomes help counteracting long-branch attraction in the deep phylogeny of gastropod mollusks
- 2019
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Ingår i: Molecular Phylogenetics and Evolution. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1055-7903 .- 1095-9513. ; 133, s. 12-23
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Tidskriftsartikel (refereegranskat)abstract
- Long-branch attraction (LBA) is a well-known artifact in phylogenetic reconstruction. Sparse taxon sampling and extreme heterogeneity of evolutionary rates among lineages generate propitious situations for LBA, even defying probabilistic methods of phylogenetic inference. A clear example illustrating LBA challenges is the difficulty of reconstructing the deep gastropod phylogeny, particularly using mitochondrial (mt) genomes. Previous studies consistently obtained unorthodox phylogenetic relationships due to the LBA between the mitogenomes of patellogastropods (true limpets, represented only by Lottia digitalis), heterobranchs, and outgroup taxa. Here, we use the reconstruction of the gastropod mitogenomic phylogeny as a case exercise to test the effect of key methodological approaches proposed to counteract LBA, including the selection of slow-evolving representatives, the use of different outgroups, the application of site-heterogeneous evolutionary models, and the removal of fast-evolving sites. In this regard, we sequenced three new patellogastropod mt genomes, which displayed shorter branches than the one of Lottia as well as gene organizations more similar to that of the hypothetical gastropod ancestor. Phylogenetic analyses incorporating the mt genomes of Patella ferruginea, Patella vulgata, and Cellana radiata allowed eliminating the artificial clustering of Patellogastropoda and Heterobranchia that had prevailed in previous studies. Furthermore, the use of site-heterogeneous models with certain combinations of lineages within the outgroup allowed eliminating also the LBA between Heterobranchia and the outgroup, and recovering Apogastropoda (i.e., Caenogastropoda + Heterobranchia). Hence, for the first time, we were able to obtain a mitogenomic phylogeny of gastropods that is congruent with both morphological and nuclear datasets.
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