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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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| 2. |
- Chibueze, J. O., et al.
(författare)
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A MeerKAT, e-MERLIN, HESS, and Swift search for persistent and transient emission associated with three localized FRBs
- 2022
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 515:1, s. 1365-1379
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Tidskriftsartikel (refereegranskat)abstract
- We report on a search for persistent radio emission from the one-off fast radio burst (11(B) 20190714A, as well as from two repeating FRBs, 20190711A and 20171019A, using the MeerKAT radio telescope. For FRB 20171019A, we also conducted simultaneous observations with the High-Energy Stereoscopic System (H.E.S.S.) in very high-energy gamma rays and searched for signals in the ultraviolet, optical, and X-ray bands. For this FRB, we obtain a UV flux upper limit of 1.39 x 10(-16) erg cm(-2) s(-1) angstrom(-1), X-ray limit of similar to 6.6 x 10(-14) erg cm(-2) s(-1) and a limit on the very high energy gamma-ray flux Phi(E > 120 GeV) < 1.7 x 10(-12) erg cm(-2) S-1. We obtain a radio upper limit of similar to 15 mu Jy beam(-1) for persistent emission at the locations of both FRBs 20190711A and 20171019A with MeerKAT. However, we detected an almost unresolved (ratio of integrated flux to peak flux is similar to 1.7 beam) radio emission, where the synthesized beam size was similar to 8 arcsec size with a peak brightness of similar to 53 mu Jy beam(-1) at MeerKAT and similar to 86 mu Jy beam(-1) at e-MERLIN, possibly associated with FRB 20190714A at z = 0.2365. This represents the first detection of persistent continuum radio emission potentially associated with a (as-yet) non- repeating FRB. If the association is confirmed, one of the strongest remaining distinction between repeaters and non-repeaters would no longer be applicable. A parallel search for repeat bursts from these FRBs revealed no new detections down to a fluence of 0.08 Jy ms for a 1 ms duration burst.
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