Investigation of genetic determinants of cognitive change in later life

Liam Mahedy; Emma L Anderson; Kate M Tilling; Zak Thornton; Andrew Elmore; Sandor Szalma; Arthur Simen; Meredith Culp; Stephen Zicha; Brian Harel; George Davey Smith; Erin N Smith; Lavinia Paternoster

doi:10.1038/s41398-023-02726-6

Investigation of genetic determinants of cognitive change in later life

Liam Mahedy, Emma L Anderson, Kate M Tilling, Zak Thornton, Andrew Elmore, Sandor Szalma, Arthur Simen, Meredith Culp, Stephen Zicha, Brian Harel, George Davey Smith, Erin N Smith, Lavinia Paternoster^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

2 Citations (Scopus)

Abstract

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.

Original language	English
Article number	31
Number of pages	11
Journal	Translational Psychiatry
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41398-023-02726-6
Publication status	Published - 18 Jan 2024

Bibliographical note

Funding Information:
The authors thank the participants of the TOMMORROW Trial. This study was funded through a collaboration with Takeda Development Center Americas. Takeda Development Center Americas had a role in the conduct of the study, data management, and analysis. LM, ELA, KT, ZAT, GDS and LP work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1 and MC_UU_00011/3). ELA is funded by a UKRI Future Leaders Fellowship (MR/W011581/1). This study was supported by the National Institute for Health and Care Research Bristol Biomedical Research Centre (NIHR203315). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. ZAT receives funding from Southmead Hospital Charitable Funds: Brain Tumour Bank and Research Fund 8036.

Funding Information:
The authors thank the participants of the TOMMORROW Trial. This study was funded through a collaboration with Takeda Development Center Americas. Takeda Development Center Americas had a role in the conduct of the study, data management, and analysis. LM, ELA, KT, ZAT, GDS and LP work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1 and MC_UU_00011/3). ELA is funded by a UKRI Future Leaders Fellowship (MR/W011581/1). This study was supported by the National Institute for Health and Care Research Bristol Biomedical Research Centre (NIHR203315). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. ZAT receives funding from Southmead Hospital Charitable Funds: Brain Tumour Bank and Research Fund 8036.

Publisher Copyright:
© 2024, The Author(s).

Research Groups and Themes

Bristol Population Health Science Institute

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10.1038/s41398-023-02726-6Licence: CC BY

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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research
Rework of IEU 2 Tilling Programme
Tilling, K. M. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research

Cite this

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title = "Investigation of genetic determinants of cognitive change in later life",

abstract = "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.",

author = "Liam Mahedy and Anderson, {Emma L} and Tilling, {Kate M} and Zak Thornton and Andrew Elmore and Sandor Szalma and Arthur Simen and Meredith Culp and Stephen Zicha and Brian Harel and {Davey Smith}, George and Smith, {Erin N} and Lavinia Paternoster",

note = "Funding Information: The authors thank the participants of the TOMMORROW Trial. This study was funded through a collaboration with Takeda Development Center Americas. Takeda Development Center Americas had a role in the conduct of the study, data management, and analysis. LM, ELA, KT, ZAT, GDS and LP work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1 and MC_UU_00011/3). ELA is funded by a UKRI Future Leaders Fellowship (MR/W011581/1). This study was supported by the National Institute for Health and Care Research Bristol Biomedical Research Centre (NIHR203315). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. ZAT receives funding from Southmead Hospital Charitable Funds: Brain Tumour Bank and Research Fund 8036. Funding Information: The authors thank the participants of the TOMMORROW Trial. This study was funded through a collaboration with Takeda Development Center Americas. Takeda Development Center Americas had a role in the conduct of the study, data management, and analysis. LM, ELA, KT, ZAT, GDS and LP work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1 and MC_UU_00011/3). ELA is funded by a UKRI Future Leaders Fellowship (MR/W011581/1). This study was supported by the National Institute for Health and Care Research Bristol Biomedical Research Centre (NIHR203315). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. ZAT receives funding from Southmead Hospital Charitable Funds: Brain Tumour Bank and Research Fund 8036. Publisher Copyright: {\textcopyright} 2024, The Author(s).",

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doi = "10.1038/s41398-023-02726-6",

language = "English",

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T1 - Investigation of genetic determinants of cognitive change in later life

AU - Mahedy, Liam

AU - Anderson, Emma L

AU - Tilling, Kate M

AU - Thornton, Zak

AU - Elmore, Andrew

AU - Szalma, Sandor

AU - Simen, Arthur

AU - Culp, Meredith

AU - Zicha, Stephen

AU - Harel, Brian

AU - Davey Smith, George

AU - Smith, Erin N

AU - Paternoster, Lavinia

N1 - Funding Information: The authors thank the participants of the TOMMORROW Trial. This study was funded through a collaboration with Takeda Development Center Americas. Takeda Development Center Americas had a role in the conduct of the study, data management, and analysis. LM, ELA, KT, ZAT, GDS and LP work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1 and MC_UU_00011/3). ELA is funded by a UKRI Future Leaders Fellowship (MR/W011581/1). This study was supported by the National Institute for Health and Care Research Bristol Biomedical Research Centre (NIHR203315). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. ZAT receives funding from Southmead Hospital Charitable Funds: Brain Tumour Bank and Research Fund 8036. Funding Information: The authors thank the participants of the TOMMORROW Trial. This study was funded through a collaboration with Takeda Development Center Americas. Takeda Development Center Americas had a role in the conduct of the study, data management, and analysis. LM, ELA, KT, ZAT, GDS and LP work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1 and MC_UU_00011/3). ELA is funded by a UKRI Future Leaders Fellowship (MR/W011581/1). This study was supported by the National Institute for Health and Care Research Bristol Biomedical Research Centre (NIHR203315). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. ZAT receives funding from Southmead Hospital Charitable Funds: Brain Tumour Bank and Research Fund 8036. Publisher Copyright: © 2024, The Author(s).

PY - 2024/1/18

Y1 - 2024/1/18

N2 - 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.

AB - 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.

U2 - 10.1038/s41398-023-02726-6

DO - 10.1038/s41398-023-02726-6

M3 - Article (Academic Journal)

C2 - 38238328

SN - 2158-3188

VL - 14

JO - Translational Psychiatry

JF - Translational Psychiatry

IS - 1

M1 - 31

ER -

Investigation of genetic determinants of cognitive change in later life

Abstract

Bibliographical note

Research Groups and Themes

Access to Document

Handle.net

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Projects

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Rework of IEU 2 Tilling Programme

Cite this