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- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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- Bellenguez, C, et al.
(författare)
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New insights into the genetic etiology of Alzheimer's disease and related dementias
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
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Tidskriftsartikel (refereegranskat)abstract
- Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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- Coppejans, D. L., et al.
(författare)
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A Mildly Relativistic Outflow from the Energetic, Fast-rising Blue Optical Transient CSS161010 in a Dwarf Galaxy
- 2020
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 895:1
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Tidskriftsartikel (refereegranskat)abstract
- We present X-ray and radio observations of the Fast Blue Optical Transient CRTS-CSS161010 J045834-081803 (CSS161010 hereafter) at t = 69-531 days. CSS161010 shows luminous X-ray (L-x similar to 5 x 10(39) erg s(-1)) and radio (L-nu similar to 10(29) erg s(-1) Hz(-1)) emission. The radio emission peaked at similar to 100 days post-transient explosion and rapidly decayed. We interpret these observations in the context of synchrotron emission from an expanding blast wave. CSS161010 launched a mildly relativistic outflow with velocity Gamma beta c >= 0.55c at similar to 100 days. This is faster than the non-relativistic AT 2018cow (Gamma beta c similar to 0.1c) and closer to ZTF18abvkwla (Gamma beta c >= 0.3c at 63 days). The inferred initial kinetic energy of CSS161010 (E-k greater than or similar to 10(51) erg) is comparable to that of long gamma-ray bursts, but the ejecta mass that is coupled to the mildly relativistic outflow is significantly larger (similar to 0.01-.1 M-circle dot). This is consistent with the lack of observed gamma-rays. The luminous X-rays were produced by a different emission component to the synchrotron radio emission. CSS161010 is located at similar to 150 Mpc in a dwarf galaxy with stellar mass M-* similar to 10(7) M-circle dot and specific star formation rate sSFR similar to 0.3 Gyr(-1). This mass is among the lowest inferred for host galaxies of explosive transients from massive stars. Our observations of CSS161010 are consistent with an engine-driven aspherical explosion from a rare evolutionary path of a H-rich stellar progenitor, but we cannot rule out a stellar tidal disruption event on a centrally located intermediate-mass black hole. Regardless of the physical mechanism, CSS161010 establishes the existence of a new class of rare (rate < 0.4% of the local core-collapse supernova rate) H-rich transients that can launch mildly relativistic outflows.
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