| 1. |
- Cruz, Raquel, et al.
(författare)
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Novel genes and sex differences in COVID-19 severity
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 31:22, s. 3789-3806
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Tidskriftsartikel (refereegranskat)abstract
- Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
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| 2. |
- Lau, Angus, et al.
(författare)
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alpha-Synuclein strains target distinct brain regions and cell types
- 2020
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Ingår i: Nature Neuroscience. - : NATURE PUBLISHING GROUP. - 1097-6256 .- 1546-1726. ; 23, s. 21-31
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Tidskriftsartikel (refereegranskat)abstract
- The clinical and pathological differences between synucleinopathies such as Parkinson's disease and multiple system atrophy have been postulated to stem from unique strains of alpha-synuclein aggregates, akin to what occurs in prion diseases. Here we demonstrate that inoculation of transgenic mice with different strains of recombinant or brain-derived alpha-synuclein aggregates produces clinically and pathologically distinct diseases. Strain-specific differences were observed in the signs of neurological illness, time to disease onset, morphology of cerebral alpha-synuclein deposits and the conformational properties of the induced aggregates. Moreover, different strains targeted distinct cellular populations and cell types within the brain, recapitulating the selective targeting observed among human synucleinopathies. Strain-specific clinical, pathological and biochemical differences were faithfully maintained after serial passaging, which implies that alpha-synuclein propagates via prion-like conformational templating. Thus, pathogenic alpha-synuclein exhibits key hallmarks of prion strains, which provides evidence that disease heterogeneity among the synucleinopathies is caused by distinct alpha-synuclein strains.
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| 3. |
- Ruiz-Riquelme, Alejandro, et al.
(författare)
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A beta 43 aggregates exhibit enhanced prion-like seeding activity in mice
- 2021
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Ingår i: Acta neuropathologica communications. - : BMC. - 2051-5960. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- When injected into genetically modified mice, aggregates of the amyloid-beta (A beta) peptide from the brains of Alzheimers disease (AD) patients or transgenic AD mouse models seed cerebral A beta deposition in a prion-like fashion. Within the brain, A beta exists as a pool of distinct C-terminal variants with lengths ranging from 37 to 43 amino acids, yet the relative contribution of individual C-terminal A beta variants to the seeding behavior of A beta aggregates remains unknown. Here, we have investigated the relative seeding activities of A beta aggregates composed exclusively of recombinant A beta 38, A beta 40, A beta 42, or A beta 43. Cerebral A beta 42 levels were not increased in App(NL-F) knock-in mice injected with A beta 38 or A beta 40 aggregates and were only increased in a subset of mice injected with A beta 42 aggregates. In contrast, significant accumulation of A beta 42 was observed in the brains of all mice inoculated with A beta 43 aggregates, and the extent of A beta 42 induction was comparable to that in mice injected with brain-derived A beta seeds. Mice inoculated with A beta 43 aggregates exhibited a distinct pattern of cerebral A beta pathology compared to mice injected with brain-derived A beta aggregates, suggesting that recombinant A beta 43 may polymerize into a unique strain. Our results indicate that aggregates containing longer A beta C-terminal variants are more potent inducers of cerebral A beta deposition and highlight the potential role of A beta 43 seeds as a crucial factor in the initial stages of A beta pathology in AD.
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