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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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- 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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- Vidal-Royo, O., et al.
(författare)
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Structural evolution of Pico del Aguila anticline (External Sierras, southern Pyrenees) derived from sandbox, numerical and 3D structural modelling techniques
- 2013
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Ingår i: Geologica Acta. - 1695-6133 .- 1696-5728. ; 11:1, s. 1-26
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Tidskriftsartikel (refereegranskat)abstract
- This paper reports on the integration of different modelling techniques to construct a unified conceptual model of structural evolution of the Pico del Aguila anticline (External Sierras, southern Pyrenees, Spain). The structure is a well-known example of a detachment fold, which exhibits a N-S structural trend, perpendicular to the general structural trend of the southern Pyrenees (mainly E-W). Based on field observations of an unevenly distributed Triassic decollement, analogue modelling shows how to generate orogen-perpendicular structures which may result in transverse anticlines. The models show how contrasts between high and low friction patches in the basal decollement led to the formation of structures at high angle, centered over the high friction areas. Numerical models investigate the effect of a complex mechanical stratigraphy, characterized by an interlayering of competent and incompetent layers, plus syn-kinematic sedimentation in the fold growth. Based on field data and seismic interpretations, a 3D reconstruction and sequential geomechanical restoration of the Pico del Aguila anticline suggests the coexistence of multiple folding mechanisms occurring simultaneously in different units and structural domains of the fold, leading to a complex strain pattern that can not be assessed by simplistic kinematic 2D approaches. By integrating the models with previous data in the region, the benefits and drawbacks of each modelling technique are discussed and an integrated model of structural evolution for the Pico del Aguila anticline is presented. This enables a better comprehension of the structure as well as of the processes that drove the evolution of the N-S detachment anticlines in the External Sierras of the southern Pyrenees.
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