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

Bernard Fongang, Muralidharan Sargurupremraj, Xueqiu Jian, Aniket Mishra, Vincent Damotte, Itziar de Rojas, Olivia Skrobot, Joshua C. Bis, Kang Hsien Fan, Erin Jacobsen, Gloria Hoi Yee Li, Jingyun Yang, Bizzarro Alessandra, Lauria Alessandra, Saima Hilal, Joyce Ruifen Chong, Yuek Ling Chai, M. J. Knol, Maria Pina Concas, Girotto GiorgiaMoeen Riaz, Chenglong Yu, Alexander Guojonsson, Paul Lacaze, Adam C. Naj, Monica Gireud-Goss, Yannick N. Wadop, Aicha Soumare, Vincent Bouteloup, Vilmundur Gudnason, Petronilla Battista, Aurora Santin, Beatrice Spedicati, Rodolfo Sardone, Lenore Launer, Jan Bressler, Rebecca F. Gottesman, Quentin Le Grand, Ilana Caro, Gennady V. Roshchupkin, Hampton L. Leonard, Chaojie Yang, Traci M. Bartz, Constance Bordes, Sigurdur Sigurdsson, María Eugenia Sáez, Børge G. Nordestgaard, Ruth Frikke-Schmidt, Anne Tybjærg-Hansen, Jonas Bille Nielsen, The Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium

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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.

Original languageEnglish
JournalAlzheimer's and Dementia
Volume20
Issue number9
Pages (from-to)5973-5995
Number of pages23
ISSN1552-5260
DOIs
Publication statusPublished - 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Keywords

  • all-cause dementia
  • Alzheimer's disease
  • cross-ancestry
  • genome-wide association study (GWAS)
  • GWAS meta-analysis
  • vascular dementia

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