Investigation of genetic determinants of cognitive change in later life.

Autor: Mahedy L; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.; Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK., Anderson EL; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.; Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK., Tilling K; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.; Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.; NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston, NHS Foundation Trust and University of Bristol, Bristol, BS8 2BN, UK., Thornton ZA; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.; Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK., Elmore AR; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.; Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.; NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston, NHS Foundation Trust and University of Bristol, Bristol, BS8 2BN, UK., Szalma S; Takeda Development Center Americas, Inc., San Diego, CA, USA., Simen A; Takeda Development Center Americas, Inc., Cambridge, MA, USA., Culp M; Takeda Development Center Americas, Inc., Cambridge, MA, USA., Zicha S; Takeda Development Center Americas, Inc., Cambridge, MA, USA., Harel BT; Takeda Development Center Americas, Inc., Cambridge, MA, USA., Davey Smith G; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.; Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.; NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston, NHS Foundation Trust and University of Bristol, Bristol, BS8 2BN, UK., Smith EN; Takeda Development Center Americas, Inc., San Diego, CA, USA., Paternoster L; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK. lavinia.paternoster@bristol.ac.uk.; Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK. lavinia.paternoster@bristol.ac.uk.; NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston, NHS Foundation Trust and University of Bristol, Bristol, BS8 2BN, UK. lavinia.paternoster@bristol.ac.uk.
Jazyk: angličtina
Zdroj: Translational psychiatry [Transl Psychiatry] 2024 Jan 18; Vol. 14 (1), pp. 31. Date of Electronic Publication: 2024 Jan 18.
DOI: 10.1038/s41398-023-02726-6
Abstrakt: Cognitive decline is a major health concern and identification of genes that may serve as drug targets to slow decline is important to adequately support an aging population. Whilst genetic studies of cross-sectional cognition have been carried out, cognitive change is less well-understood. Here, using data from the TOMMORROW trial, we investigate genetic associations with cognitive change in a cognitively normal older cohort. We conducted a genome-wide association study of trajectories of repeated cognitive measures (using generalised estimating equation (GEE) modelling) and tested associations with polygenic risk scores (PRS) of potential risk factors. We identified two genetic variants associated with change in attention domain scores, rs534221751 (p = 1 × 10 -8 with slope 1) and rs34743896 (p = 5 × 10 -10 with slope 2), implicating NCAM2 and CRIPT/ATP6V1E2 genes, respectively. We also found evidence for the association between an education PRS and baseline cognition (at >65 years of age), particularly in the language domain. We demonstrate the feasibility of conducting GWAS of cognitive change using GEE modelling and our results suggest that there may be novel genetic associations for cognitive change that have not previously been associated with cross-sectional cognition. We also show the importance of the education PRS on cognition much later in life. These findings warrant further investigation and demonstrate the potential value of using trial data and trajectory modelling to identify genetic variants associated with cognitive change.
(© 2024. The Author(s).)
Databáze: MEDLINE
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