TY - JOUR
T1 - A genome-wide association meta-analysis of all-cause and vascular dementia
AU - The Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium
AU - Fongang, Bernard
AU - Sargurupremraj, Muralidharan
AU - Jian, Xueqiu
AU - Mishra, Aniket
AU - Damotte, Vincent
AU - de Rojas, Itziar
AU - Skrobot, Olivia
AU - Bis, Joshua C.
AU - Fan, Kang Hsien
AU - Jacobsen, Erin
AU - Li, Gloria Hoi Yee
AU - Yang, Jingyun
AU - Alessandra, Bizzarro
AU - Alessandra, Lauria
AU - Hilal, Saima
AU - Chong, Joyce Ruifen
AU - Chai, Yuek Ling
AU - Knol, M. J.
AU - Concas, Maria Pina
AU - Giorgia, Girotto
AU - Riaz, Moeen
AU - Yu, Chenglong
AU - Guojonsson, Alexander
AU - Lacaze, Paul
AU - Naj, Adam C.
AU - Gireud-Goss, Monica
AU - Wadop, Yannick N.
AU - Soumare, Aicha
AU - Bouteloup, Vincent
AU - Gudnason, Vilmundur
AU - Battista, Petronilla
AU - Santin, Aurora
AU - Spedicati, Beatrice
AU - Sardone, Rodolfo
AU - Launer, Lenore
AU - Bressler, Jan
AU - Gottesman, Rebecca F.
AU - Grand, Quentin Le
AU - Caro, Ilana
AU - Roshchupkin, Gennady V.
AU - Leonard, Hampton L.
AU - Yang, Chaojie
AU - Bartz, Traci M.
AU - Bordes, Constance
AU - Ridker, Paul M.
AU - Geerlings, Mirjam I.
AU - Gasca, Natalie C.
AU - Manichaikul, Ani
AU - Nalls, Mike A.
AU - Grimmer, Timo
N1 - Publisher Copyright:
© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2024/9
Y1 - 2024/9
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - GWAS meta-analysis
KW - all-cause dementia
KW - cross-ancestry
KW - genome-wide association study (GWAS)
KW - vascular dementia
UR - https://www.scopus.com/pages/publications/85199503848
U2 - 10.1002/alz.14115
DO - 10.1002/alz.14115
M3 - Article
C2 - 39046104
AN - SCOPUS:85199503848
SN - 1552-5260
VL - 20
SP - 5973
EP - 5995
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 9
ER -
SDG 3 Good Health and Well-being