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

The Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium; 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 Giorgia; Moeen 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; Paul M. Ridker; Mirjam I. Geerlings; Natalie C. Gasca; Ani Manichaikul; Mike A. Nalls; Pekka Karhunen

doi:10.1002/alz.14115

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

The Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium
, 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 Giorgia, Moeen 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, Paul M. Ridker, Mirjam I. Geerlings, Natalie C. Gasca, Ani Manichaikul, Mike A. Nalls, Pekka Karhunen

Research output: Contribution to journal › Article › Scientific › peer-review

42 Citations (Scopus)

13 Downloads (Pure)

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 language	English
Pages (from-to)	5973-5995
Number of pages	23
Journal	Alzheimer's and Dementia
Volume	20
Issue number	9
DOIs	https://doi.org/10.1002/alz.14115
Publication status	Published - Sept 2024
Publication type	A1 Journal article-refereed

Funding

We thank the many study participants, researchers, and staff for collecting and contributing to the data. This project was conducted within the neurology working group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. The CHARGE cohorts are supported in part by the National Heart, Lung, and Blood Institute (NHLBI) infrastructure grants R01HL105756 (Psaty), RC2HL102419 (Boerwinkle) and the neurology working group is supported by the National Institute on Aging (NIA) R01 grant AG033193. Additional funding sources include the UT Health San Antonio Center for Biomedical Neuroscience (CBN) and grants from the NIA (AG059421, AG054076, AG049607, AG033090, AG066524, P30 AG066546, 5P30AG059305\u201003, RF1 AG061729A1, 5U01AG052409\u201004) and NINDS (NS017950, UF1NS125513, K01NS126489). Funding sources for each cohort are listed in Supplementary File 2 . Agustin Ruiz and Itziar de Rojas acknowledge research support from Grifols SA (Spain), Fundacion Bacaria LaCaixa (Spain), Instituto de Salud Carlos III Ministry of Health (Spain), Roche, and Janssen. Agustin Ruiz received consulting fees and honoraria from Landsteiner Genmed SL, Grifols SA, and Janssen; support for attending meetings from Grifols SA; and stock options from Landsteiner Genmed SL. All authors report no conflicts of interest. Additional author disclosures are available in the supporting information (Supplementary File 2 ).

Funders	Funder number
UT Health San Antonio Center for Biomedical Neuroscience
National Heart, Lung, and Blood Institute
Roche Oy
Janssen Pharmaceutica NV
Fundacion Bacaria LaCaixa
Instituto de Salud Carlos III Ministry of Health
CBN	AG059421, 5U01AG052409‐04, AG054076, 5P30AG059305‐03, RF1 AG061729A1, P30 AG066546, AG049607, AG033090, AG066524
National Institute on Aging	AG033193
National Institute on Aging
NHLBI Framingham Heart Study	RC2HL102419, R01HL105756
National Institute of Neurological Disorders and Stroke (NINDS)	K01NS126489, NS017950, UF1NS125513

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

Publication forum classification

Publication forum level 3

ASJC Scopus subject areas

Epidemiology
Health Policy
Developmental Neuroscience
Clinical Neurology
Geriatrics and Gerontology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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10.1002/alz.14115Licence: CC BY

Alzheimer s Dementia - 2024 - - A genome‐wide association meta‐analysis of all‐cause and vascular dementiaFinal published version, 1.71 MBLicence: CC BY

https://urn.fi/URN:NBN:fi:tuni-2024111210134Licence: CC BY

Cite this

The Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium, Fongang, B., Sargurupremraj, M., Jian, X., Mishra, A., Damotte, V., de Rojas, I., Skrobot, O., Bis, J. C., Fan, K. H., Jacobsen, E., Li, G. H. Y., Yang, J., Alessandra, B., Alessandra, L., Hilal, S., Chong, J. R., Chai, Y. L., Knol, M. J., ... Karhunen, P. (2024). A genome-wide association meta-analysis of all-cause and vascular dementia. Alzheimer's and Dementia, 20(9), 5973-5995. https://doi.org/10.1002/alz.14115

@article{ed66d5de3e504dccbbf1378d4bf57f9a,

title = "A genome-wide association meta-analysis of all-cause and 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.",

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

author = "\{The Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium\} and Bernard Fongang and Muralidharan Sargurupremraj and Xueqiu Jian and Aniket Mishra and Vincent Damotte and \{de Rojas\}, Itziar and Olivia Skrobot and Bis, \{Joshua C.\} and Fan, \{Kang Hsien\} and Erin Jacobsen and Li, \{Gloria Hoi Yee\} and Jingyun Yang and Bizzarro Alessandra and Lauria Alessandra and Saima Hilal and Chong, \{Joyce Ruifen\} and Chai, \{Yuek Ling\} and Knol, \{M. J.\} and Concas, \{Maria Pina\} and Girotto Giorgia and Moeen Riaz and Chenglong Yu and Alexander Guojonsson and Paul Lacaze and Naj, \{Adam C.\} and Monica Gireud-Goss and Wadop, \{Yannick N.\} and Aicha Soumare and Vincent Bouteloup and Vilmundur Gudnason and Petronilla Battista and Aurora Santin and Beatrice Spedicati and Rodolfo Sardone and Lenore Launer and Jan Bressler and Gottesman, \{Rebecca F.\} and Grand, \{Quentin Le\} and Ilana Caro and Roshchupkin, \{Gennady V.\} and Leonard, \{Hampton L.\} and Chaojie Yang and Bartz, \{Traci M.\} and Constance Bordes and Ridker, \{Paul M.\} and Geerlings, \{Mirjam I.\} and Gasca, \{Natalie C.\} and Ani Manichaikul and Nalls, \{Mike A.\} and Pekka Karhunen",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). Alzheimer's \& Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2024",

month = sep,

doi = "10.1002/alz.14115",

language = "English",

volume = "20",

pages = "5973--5995",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley and Sons Inc",

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The Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium, Fongang, B, Sargurupremraj, M, Jian, X, Mishra, A, Damotte, V, de Rojas, I, Skrobot, O, Bis, JC, Fan, KH, Jacobsen, E, Li, GHY, Yang, J, Alessandra, B, Alessandra, L, Hilal, S, Chong, JR, Chai, YL, Knol, MJ, Concas, MP, Giorgia, G, Riaz, M, Yu, C, Guojonsson, A, Lacaze, P, Naj, AC, Gireud-Goss, M, Wadop, YN, Soumare, A, Bouteloup, V, Gudnason, V, Battista, P, Santin, A, Spedicati, B, Sardone, R, Launer, L, Bressler, J, Gottesman, RF, Grand, QL, Caro, I, Roshchupkin, GV, Leonard, HL, Yang, C, Bartz, TM, Bordes, C, Ridker, PM, Geerlings, MI, Gasca, NC, Manichaikul, A, Nalls, MA & Karhunen, P 2024, 'A genome-wide association meta-analysis of all-cause and vascular dementia', Alzheimer's and Dementia, vol. 20, no. 9, pp. 5973-5995. https://doi.org/10.1002/alz.14115

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 - Karhunen, Pekka

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 - all-cause dementia

KW - Alzheimer's disease

KW - cross-ancestry

KW - genome-wide association study (GWAS)

KW - GWAS meta-analysis

KW - vascular dementia

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 -

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

Abstract

Funding

UN SDGs

Keywords

Publication forum classification

ASJC Scopus subject areas

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