A genome-wide association meta-analysis of all-cause and vascular dementia

The Mega Vascular Cognitive Impairment, and Dementia (MEGAVCID) consortium and Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259 2024. A genome-wide association meta-analysis of all-cause and vascular dementia. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 20 (9) , pp. 5973-5995. 10.1002/alz.14115

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Abstract

INTRODUCTION Dementia is a multifactorial disease with Alzheimer's disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD. METHODS We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 individuals, with 46,902 and 8702 cases of ACD and VaD, respectively. Known AD loci for ACD and VaD were replicated. Bioinformatic analyses prioritized genes that are likely functionally relevant and shared with closely related traits and risk factors. RESULTS For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and magnetic resonance imaging markers of small vessel disease (SVD; HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). DISCUSSION Our study identified genetic risks underlying ACD, demonstrating overlap with neurodegenerative processes, vascular risk factors, and cerebral SVD. Highlights We conducted the largest genome-wide association study of all-cause dementia (ACD) and vascular dementia (VaD). Known genetic variants associated with AD were replicated for ACD and VaD. Functional analyses identified novel loci for ACD and VaD. Genetic risks of ACD overlapped with neurodegeneration, vascular risk factors, and cerebral small vessel disease.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	Julie Williams has been linked as a member of the consortium
Publisher:	Wiley
ISSN:	1552-5260
Date of First Compliant Deposit:	31 January 2025
Date of Acceptance:	20 May 2024
Last Modified:	07 Feb 2025 11:00
URI:	https://orca.cardiff.ac.uk/id/eprint/175794

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