| 1. |
- 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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| 2. |
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| 3. |
- 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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| 4. |
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| 5. |
- Davies, G., et al.
(författare)
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Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function
- 2018
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
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| 6. |
- Davies, G., et al.
(författare)
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Genetic contributions to variation in general cognitive function : a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)
- 2015
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 20:2, s. 183-192
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Tidskriftsartikel (refereegranskat)abstract
- General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health-and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N = 53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P = 3.93 x 10(-9), MIR2113; rs17522122, P = 2.55 x 10(-8), AKAP6; rs10119, P = 5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P = 1x10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N = 6617) and the Health and Retirement Study (N = 5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e. = 5%) and 28% (s.e. = 7%), respectively. Using polygenic prediction analysis, similar to 1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N = 5487; P = 1.5 x 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.
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| 7. |
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| 8. |
- Andgren, Karin, et al.
(författare)
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Recoil distance method lifetime measurements in Cd-107 and Pd-101.
- 2006
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Ingår i: Frontiers in Nuclear Structure Astrophysics, and Reactions: FINUSTAR. - MELVILLE, NY : AMER INST PHYSICS. - 0735403236 ; , s. 391-393
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Konferensbidrag (refereegranskat)abstract
- Preliminary lifetime values have been measured for a number of near-yrast states in the odd-A transitional nuclei Cd-107 and Pd-103. The reaction used to populate the nuclei of interest was Mo-98(C-12, 3nx alpha)Cd-107, Pd-103, with the beam delivered by the tandem accelerator of the Wright Nuclear Structure Laboratory at an incident beam energy of 60 MeV. Our experiment was aimed at the investigation of collective excitations built on the unnatural parity, v h(11/2) orbital, specifically by measuring the B(E2) values of decays from the excited levels built on this intrinsic structure, using the Doppler Recoil Distance Method. We report lifetimes and associated transition probabilities for decays from the 15/2(-) and the 19/2(-) states in Cd-107 and the first measurement of the 15/2- state in Pd-103. These results suggest that neither a simple rotational or vibrational interpretation is sufficient to explain the observed structures.
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| 9. |
- Ashley, S. F., et al.
(författare)
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Intrinsic state lifetimes in Pd-103 and Cd-106,Cd-107
- 2007
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 76:6, s. 064302-
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Tidskriftsartikel (refereegranskat)abstract
- The mean-lifetimes, tau, of various medium-spin excited states in Pd-103 and Cd-106,Cd-107 have been deduced using the Recoil Distance Doppler Shift technique and the Differential Decay Curve Method. In Cd-106, the mean-lifetimes of the I-pi=12(+) state at E-x=5418 keV and the I-pi=11(-) state at E-x=4324 keV have been deduced as 11.4(17)ps and 8.2(7)ps, respectively. The associated beta(2) deformation within the axially-symmetric deformed rotor model for these states are 0.14(1) and 0.14(1), respectively. The beta(2) deformation of 0.14(1) for the I-pi=12(+) state in Cd-106 compares with a predicted beta(2) value from total Routhian surface (TRS) calculations of 0.17. In addition, the mean-lifetimes of the yrast I-pi = 15(-)/2 states in Pd-103 (at E-x=1262 keV) and Cd-107 (at E-x=1360 keV) have been deduced to be 31.2(44)ps and 31.4(17)ps, respectively, corresponding to beta(2) values of 0.16(1) and 0.12(1) assuming axial symmetry. Agreement with TRS calculations are good for Pd-103 but deviate for that predicted for Cd-107.
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| 10. |
- Ashley, S. F., et al.
(författare)
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Lifetime determination of excited states in Cd-106
- 2007
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Ingår i: Acta Physica Polonica B. - 0587-4254 .- 1509-5770. ; 38:4, s. 1385-1388
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Tidskriftsartikel (refereegranskat)abstract
- Two separate experiments using the Differential Decay Curve Method have been performed to extract mean lifetimes of excited states in 106 Cd. The inedium-spin states of interest were populated by the Mo-98(C-12, 4n) Cd-106 reaction performed at the Wright Nuclear Structure Lab., Yale University. From this experiment, two isomeric state mean lifetimes have been deduced. The low-lying states were populated by the Mo-96(C-13, 3n)Cd-106 reaction performed at the Institut fur Kernphysik, Universitat zu Koln. The mean lifetime of the I-pi = 2(1)(+) state was deduced, tentatively, as 16.4(9) ps. This value differs from the previously accepted literature value from Coulomb excitation of 10.43(9) ps.
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