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- Patel, Riyaz S., et al.
(författare)
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Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium
- 2019
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Ingår i: Circulation. - 2574-8300. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
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- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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- Satizabal, Claudia L., et al.
(författare)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Tidskriftsartikel (refereegranskat)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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- Steen, Robert O., 1978-, et al.
(författare)
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Bis-cyclometallated Molecular Switches Based on 4,7-phenantroline and 1,5-naphthyridine Architecture
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Two new bis-terdentate ligands, 3,8-bis-(6-thiophen-2-yl-pyridin-2-yl)-[4,7]phenanthroline (L1) and 2,6-bis(6-(thiophen-2-yl)pyridin-2-yl)-1,5-naphthyridine (L2), capable of reversible double cyclometallation have been synthesized. Both syntheses proceeded via a Skraup synthesis followed by Stille cross-coupling with 2-thiophen-2-yl-6-tributylstannylpyridine to yield the final product. The Ru2(tpy)2-complex of L1 was shown to be capable of reversible cyclometallation, where the bis-cyclometallated (C,C) isomer of the complex had an oxidation potential of +249 mV while the oxidation potential of the doubly S-coordinated (S,S) complex was +987 mV. No ground state interaction between the Ru cores was however found. In theory the complex should display a third, mixed, state. An S,C-coordinated isomer would open the way for molecular electronic applications based on ternary logic. However, despite attempts the S,C-coordinated complex could not be generated.
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- Steen, Robert O., 1978-, et al.
(författare)
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Coordination-mode pH-activated Molecular Switches based on Ruthenium(II) Oligopyridine Complex Architecture
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- A number of [Ru(tpy)L] complexes (where L is a ligand based on the 6-thien-2-yl-2,2’-bipyridine motif) have been generated to study the ability of this terdentate motif to switch between a N,N,C and a N,N,S binding mode as a function of pH and irradiation. Whilst the parent system 6-thien-2-yl-2,2’-bipyridine (1) displayed facile switching between the orange and purple forms, heavier analogues displayed sluggish switching – most likely resulting from a large moment of inertia about the bond between the S/C-bonded thiophene ring and the chelating bipyridine unit. Prototypic unsymmetrical bimetallic complexes (C7S and C7C) have been generated in order to test if the binding mode of the switching unit can affect the oxidation potential of the remote [Ru(bpy)2(L)] unit. The results of cyclic voltammetry studies suggest that only weak electronic coupling between the metal cores exists, and that the coordination mode (N,N,C or N,N,S) of the thiophene moiety only has a small effect on the oxidation potential of the [Ru(bpy)2(L)] unit.
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