A Genome-Wide Association Meta-Analysis of All-Cause and Vascular Dementia

Authors

Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) Consortium

Publication Date

9-1-2024

Journal

Alzheimer's & Dementia

DOI

10.1002/alz.14115

PMID

39046104

PMCID

PMC11497727

PubMedCentral® Posted Date

7-24-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Alzheimer Disease, Dementia, Dementia, Vascular, Genetic Predisposition to Disease, Genome-Wide Association Study, Risk Factors, all‐cause dementia, Alzheimer's disease, cross‐ancestry, genome‐wide association study (GWAS), GWAS meta‐analysis, vascular dementia

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.