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 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; 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

doi:10.1002/alz.14115

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

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

2 Citationer (Scopus)

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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.

Originalsprog	Engelsk
Tidsskrift	Alzheimer's and Dementia
Vol/bind	20
Udgave nummer	9
Sider (fra-til)	5973-5995
Antal sider	23
ISSN	1552-5260
DOI	https://doi.org/10.1002/alz.14115
Status	Udgivet - 2024

Bibliografisk note

Funding Information:
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 .

Funding Information:
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 ).

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

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10.1002/alz.14115Licens: CC BY

Full textForlagets udgivne version, 1,75 MBLicens: CC BY

Citationsformater

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., Concas, M. P., ... The Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium (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

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

I: Alzheimer's and Dementia, Bind 20, Nr. 9, 2024, s. 5973-5995.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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, Sigurdsson, S, Sáez, ME, Nordestgaard, BG , Frikke-Schmidt, R , Tybjærg-Hansen, A, Nielsen, JB & The Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium 2024, 'A genome-wide association meta-analysis of all-cause and vascular dementia', Alzheimer's and Dementia, bind 20, nr. 9, s. 5973-5995. https://doi.org/10.1002/alz.14115

Fongang, Bernard ; Sargurupremraj, Muralidharan ; Jian, Xueqiu ; Mishra, Aniket ; Damotte, Vincent ; de Rojas, Itziar ; Skrobot, Olivia ; Bis, Joshua C. ; Fan, Kang Hsien ; Jacobsen, Erin ; Li, Gloria Hoi Yee ; Yang, Jingyun ; Alessandra, Bizzarro ; Alessandra, Lauria ; Hilal, Saima ; Chong, Joyce Ruifen ; Chai, Yuek Ling ; Knol, M. J. ; Concas, Maria Pina ; Giorgia, Girotto ; Riaz, Moeen ; Yu, Chenglong ; Guojonsson, Alexander ; Lacaze, Paul ; Naj, Adam C. ; Gireud-Goss, Monica ; Wadop, Yannick N. ; Soumare, Aicha ; Bouteloup, Vincent ; Gudnason, Vilmundur ; Battista, Petronilla ; Santin, Aurora ; Spedicati, Beatrice ; Sardone, Rodolfo ; Launer, Lenore ; Bressler, Jan ; Gottesman, Rebecca F. ; Grand, Quentin Le ; Caro, Ilana ; Roshchupkin, Gennady V. ; Leonard, Hampton L. ; Yang, Chaojie ; Bartz, Traci M. ; Bordes, Constance ; Sigurdsson, Sigurdur ; Sáez, María Eugenia ; Nordestgaard, Børge G. ; Frikke-Schmidt, Ruth ; Tybjærg-Hansen, Anne ; Nielsen, Jonas Bille ; The Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium. / A genome-wide association meta-analysis of all-cause and vascular dementia. I: Alzheimer's and Dementia. 2024 ; Bind 20, Nr. 9. s. 5973-5995.

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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 = "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 Sigurdur Sigurdsson and S{\'a}ez, {Mar{\'i}a Eugenia} and Nordestgaard, {B{\o}rge G.} and Ruth Frikke-Schmidt and Anne Tybj{\ae}rg-Hansen and Nielsen, {Jonas Bille} and {The Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium}",

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

year = "2024",

doi = "10.1002/alz.14115",

language = "English",

volume = "20",

pages = "5973--5995",

journal = "Alzheimer's & Dementia",

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TY - JOUR

T1 - A genome-wide association meta-analysis of all-cause and vascular dementia

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 - Sigurdsson, Sigurdur

AU - Sáez, María Eugenia

AU - Nordestgaard, Børge G.

AU - Frikke-Schmidt, Ruth

AU - Tybjærg-Hansen, Anne

AU - Nielsen, Jonas Bille

AU - The Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium

PY - 2024

Y1 - 2024

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 - Journal article

C2 - 39046104

AN - SCOPUS:85199503848

VL - 20

SP - 5973

EP - 5995

JO - Alzheimer's & Dementia

JF - Alzheimer's & Dementia

SN - 1552-5260

IS - 9

ER -