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- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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- Pulit, S. L., et al.
(författare)
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Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes
- 2018
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Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 4:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
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- Wang, HD, et al.
(författare)
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Global, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015
- 2016
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Ingår i: Lancet (London, England). - : Elsevier. - 1474-547X .- 0140-6736. ; 388:10053, s. 1725-1774
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Tidskriftsartikel (refereegranskat)
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- Björck, Svante, et al.
(författare)
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A Holocene lacustrine record in the central North Atlantic: proxies for volcanic activity, short-term NAO mode variability, and long-term precipitation changes
- 2006
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791. ; 25:1-2, s. 9-32
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Tidskriftsartikel (refereegranskat)abstract
- Lake and peat corings on three Azores islands in the central North Atlantic, resulted in the discovery of a 6000 year long lacustrine sequence in a small crater lake, Lake Caveiro, on the island of Pico. This island is dominated by Pico mountain (2351 m), Portugal's highest mountain, and the lake site is situated at 903 in asl. Two sediment profiles, one central and one littoral, were sampled. Due to large facial shifts and disconformities in the littoral cores the analyses were concentrated on the central core; only the earliest 1000 years of the littoral core were studied to complement the central profile. We used sedimentology, geochemistry, diatom analyses, magnetic properties, and multivariate statistics, together with C-14 and Pb-210 dating techniques, to analyse the environmental history of the lake. Volcanic activity seems to have had a dominating impact on sediment changes and partly also on the diatom assemblages; a large number of tephras are found and seem to be connected with large (diatom) inferred pH variations. However, by a combination of methods, including multivariate techniques, we infer that precipitation changes can be detected through the volcanic noise. In the youngest part of the record (AD 1600-2000), with its decadal resolution, these humidity variations seem partly related to shifts in dominating NAO mode. The more long-term precipitation changes further back in time (350-5100 cal yr BP) roughly correspond to the well-known North Atlantic drift-ice variations as well as other North Atlantic records; low precipitation during drift-ice periods. We think these alterations were driven by changes in the thermolialine circulation as large-scale equivalences to the Great Salt Anomaly; low sea surface A temperatures and changes in circulation patterns of the central North Atlantic decreased the regional precipitation. Cooler/drier periods occurred 400-800, 1300-1800, 2600-3000, 3300-3400 and possibly also 4400-4600 cal yr BP,. while 300-400, 900-1000, 2000-2400, 3100-3200, 3800-4000 and 4700-5000 cal yr BP seem to have been more humid phases on the Azores. (c) 2005 Elsevier Ltd. All rights reserved.
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