Ancestry-related differences in chromatin accessibility and gene expression of APOE ε4 are associated with Alzheimer's disease risk

Katrina Celis; Maria D.M.Muniz Moreno; Farid Rajabli; Patrice Whitehead; Kara Hamilton-Nelson; Derek M. Dykxhoorn; Karen Nuytemans; Liyong Wang; Margaret Ellen Flanagan; Sandra Weintraub; Changiz Geula; Marla Gearing; Clifton L. Dalgard; Fulai Jin; David A. Bennett; Theresa Schuck; Margaret A. Pericak-Vance; Anthony J. Griswold; Juan I. Young; Jeffery M. Vance

doi:10.1002/alz.13075

Ancestry-related differences in chromatin accessibility and gene expression of APOE ε4 are associated with Alzheimer's disease risk

Katrina Celis, Maria D.M.Muniz Moreno, Farid Rajabli, Patrice Whitehead, Kara Hamilton-Nelson, Derek M. Dykxhoorn, Karen Nuytemans, Liyong Wang, Margaret Ellen Flanagan, Sandra Weintraub, Changiz Geula, Marla Gearing, Clifton L. Dalgard, Fulai Jin, David A. Bennett, Theresa Schuck, Margaret A. Pericak-Vance, Anthony J. Griswold, Juan I. Young, Jeffery M. Vance^*

^*Corresponding author for this work

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

Abstract

Introduction: European local ancestry (ELA) surrounding apolipoprotein E (APOE) ε4 confers higher risk for Alzheimer's disease (AD) compared to African local ancestry (ALA). We demonstrated significantly higher APOE ε4 expression in ELA versus ALA in AD brains from APOE ε4/ε4 carriers. Chromatin accessibility differences could contribute to these expression changes. Methods: We performed single nuclei assays for transposase accessible chromatin sequencing from the frontal cortex of six ALA and six ELA AD brains, homozygous for local ancestry and APOE ε4. Results: Our results showed an increased chromatin accessibility at the APOE ε4 promoter area in ELA versus ALA astrocytes. This increased accessibility in ELA astrocytes extended genome wide. Genes with increased accessibility in ELA in astrocytes were enriched for synapsis, cholesterol processing, and astrocyte reactivity. Discussion: Our results suggest that increased chromatin accessibility of APOE ε4 in ELA astrocytes contributes to the observed elevated APOE ε4 expression, corresponding to the increased AD risk in ELA versus ALA APOE ε4/ε4 carriers.

Original language	English (US)
Journal	Alzheimer's and Dementia
DOIs	https://doi.org/10.1002/alz.13075
State	Accepted/In press - 2023

Keywords

African
Alzheimer's disease
European
ancestry
apolipoprotein E ε4
chromatin accessibility
gene expression
single nuclei assay for transposase accessible chromatin followed by sequencing
single nucleus RNA sequencing

ASJC Scopus subject areas

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

UN SDGs

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

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10.1002/alz.13075

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Celis, K., Moreno, M. D. M. M., Rajabli, F., Whitehead, P., Hamilton-Nelson, K., Dykxhoorn, D. M., Nuytemans, K., Wang, L., Flanagan, M. E., Weintraub, S., Geula, C., Gearing, M., Dalgard, C. L., Jin, F., Bennett, D. A., Schuck, T., Pericak-Vance, M. A., Griswold, A. J., Young, J. I., & Vance, J. M. (Accepted/In press). Ancestry-related differences in chromatin accessibility and gene expression of APOE ε4 are associated with Alzheimer's disease risk. Alzheimer's and Dementia. https://doi.org/10.1002/alz.13075

@article{bc20b6126d7e424ebaae127ca76711b3,

title = "Ancestry-related differences in chromatin accessibility and gene expression of APOE ε4 are associated with Alzheimer's disease risk",

abstract = "Introduction: European local ancestry (ELA) surrounding apolipoprotein E (APOE) ε4 confers higher risk for Alzheimer's disease (AD) compared to African local ancestry (ALA). We demonstrated significantly higher APOE ε4 expression in ELA versus ALA in AD brains from APOE ε4/ε4 carriers. Chromatin accessibility differences could contribute to these expression changes. Methods: We performed single nuclei assays for transposase accessible chromatin sequencing from the frontal cortex of six ALA and six ELA AD brains, homozygous for local ancestry and APOE ε4. Results: Our results showed an increased chromatin accessibility at the APOE ε4 promoter area in ELA versus ALA astrocytes. This increased accessibility in ELA astrocytes extended genome wide. Genes with increased accessibility in ELA in astrocytes were enriched for synapsis, cholesterol processing, and astrocyte reactivity. Discussion: Our results suggest that increased chromatin accessibility of APOE ε4 in ELA astrocytes contributes to the observed elevated APOE ε4 expression, corresponding to the increased AD risk in ELA versus ALA APOE ε4/ε4 carriers.",

keywords = "African, Alzheimer's disease, European, ancestry, apolipoprotein E ε4, chromatin accessibility, gene expression, single nuclei assay for transposase accessible chromatin followed by sequencing, single nucleus RNA sequencing",

author = "Katrina Celis and Moreno, {Maria D.M.Muniz} and Farid Rajabli and Patrice Whitehead and Kara Hamilton-Nelson and Dykxhoorn, {Derek M.} and Karen Nuytemans and Liyong Wang and Flanagan, {Margaret Ellen} and Sandra Weintraub and Changiz Geula and Marla Gearing and Dalgard, {Clifton L.} and Fulai Jin and Bennett, {David A.} and Theresa Schuck and Pericak-Vance, {Margaret A.} and Griswold, {Anthony J.} and Young, {Juan I.} and Vance, {Jeffery M.}",

note = "Funding Information: We acknowledge the collaboration of Dr. John Q. Trojanowski in this study, whose untimely death is a great loss to both his family and colleagues and to the field of neurodegeneration research. This study was supported by the National Institute of Health (grant numbers R01‐AG059018, U01‐AG052410, U01‐AG057659, U01AG072579, and R01‐AG015819), the Alzheimer's Disease Center (ADC) networks (NIA; grant number AG054074), the BrightFocus Foundation, and Alzheimer's Association (grant number A2018425S). The work was also funded by the National Institutes of Health (grant number P50‐AG0256878 and P30‐AG013854) from Emory and Northwestern, as well as from the Alzheimer's Disease Core Center grant (P30AG010161) from Rush Alzheimer's Disease Center. Genomic and data analysis was provided by the Center for Genome Technology (CGT) from the John P. Hussman Institute for Human Genomics (HIHG). Publisher Copyright: {\textcopyright} 2023 the Alzheimer's Association.",

year = "2023",

doi = "10.1002/alz.13075",

language = "English (US)",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "Elsevier Inc.",

}

Celis, K, Moreno, MDMM, Rajabli, F, Whitehead, P, Hamilton-Nelson, K, Dykxhoorn, DM, Nuytemans, K, Wang, L, Flanagan, ME, Weintraub, S , Geula, C, Gearing, M, Dalgard, CL, Jin, F, Bennett, DA, Schuck, T, Pericak-Vance, MA, Griswold, AJ, Young, JI & Vance, JM 2023, 'Ancestry-related differences in chromatin accessibility and gene expression of APOE ε4 are associated with Alzheimer's disease risk', Alzheimer's and Dementia. https://doi.org/10.1002/alz.13075

TY - JOUR

T1 - Ancestry-related differences in chromatin accessibility and gene expression of APOE ε4 are associated with Alzheimer's disease risk

AU - Celis, Katrina

AU - Moreno, Maria D.M.Muniz

AU - Rajabli, Farid

AU - Whitehead, Patrice

AU - Hamilton-Nelson, Kara

AU - Dykxhoorn, Derek M.

AU - Nuytemans, Karen

AU - Wang, Liyong

AU - Flanagan, Margaret Ellen

AU - Weintraub, Sandra

AU - Geula, Changiz

AU - Gearing, Marla

AU - Dalgard, Clifton L.

AU - Jin, Fulai

AU - Bennett, David A.

AU - Schuck, Theresa

AU - Pericak-Vance, Margaret A.

AU - Griswold, Anthony J.

AU - Young, Juan I.

AU - Vance, Jeffery M.

N1 - Funding Information: We acknowledge the collaboration of Dr. John Q. Trojanowski in this study, whose untimely death is a great loss to both his family and colleagues and to the field of neurodegeneration research. This study was supported by the National Institute of Health (grant numbers R01‐AG059018, U01‐AG052410, U01‐AG057659, U01AG072579, and R01‐AG015819), the Alzheimer's Disease Center (ADC) networks (NIA; grant number AG054074), the BrightFocus Foundation, and Alzheimer's Association (grant number A2018425S). The work was also funded by the National Institutes of Health (grant number P50‐AG0256878 and P30‐AG013854) from Emory and Northwestern, as well as from the Alzheimer's Disease Core Center grant (P30AG010161) from Rush Alzheimer's Disease Center. Genomic and data analysis was provided by the Center for Genome Technology (CGT) from the John P. Hussman Institute for Human Genomics (HIHG). Publisher Copyright: © 2023 the Alzheimer's Association.

PY - 2023

Y1 - 2023

N2 - Introduction: European local ancestry (ELA) surrounding apolipoprotein E (APOE) ε4 confers higher risk for Alzheimer's disease (AD) compared to African local ancestry (ALA). We demonstrated significantly higher APOE ε4 expression in ELA versus ALA in AD brains from APOE ε4/ε4 carriers. Chromatin accessibility differences could contribute to these expression changes. Methods: We performed single nuclei assays for transposase accessible chromatin sequencing from the frontal cortex of six ALA and six ELA AD brains, homozygous for local ancestry and APOE ε4. Results: Our results showed an increased chromatin accessibility at the APOE ε4 promoter area in ELA versus ALA astrocytes. This increased accessibility in ELA astrocytes extended genome wide. Genes with increased accessibility in ELA in astrocytes were enriched for synapsis, cholesterol processing, and astrocyte reactivity. Discussion: Our results suggest that increased chromatin accessibility of APOE ε4 in ELA astrocytes contributes to the observed elevated APOE ε4 expression, corresponding to the increased AD risk in ELA versus ALA APOE ε4/ε4 carriers.

AB - Introduction: European local ancestry (ELA) surrounding apolipoprotein E (APOE) ε4 confers higher risk for Alzheimer's disease (AD) compared to African local ancestry (ALA). We demonstrated significantly higher APOE ε4 expression in ELA versus ALA in AD brains from APOE ε4/ε4 carriers. Chromatin accessibility differences could contribute to these expression changes. Methods: We performed single nuclei assays for transposase accessible chromatin sequencing from the frontal cortex of six ALA and six ELA AD brains, homozygous for local ancestry and APOE ε4. Results: Our results showed an increased chromatin accessibility at the APOE ε4 promoter area in ELA versus ALA astrocytes. This increased accessibility in ELA astrocytes extended genome wide. Genes with increased accessibility in ELA in astrocytes were enriched for synapsis, cholesterol processing, and astrocyte reactivity. Discussion: Our results suggest that increased chromatin accessibility of APOE ε4 in ELA astrocytes contributes to the observed elevated APOE ε4 expression, corresponding to the increased AD risk in ELA versus ALA APOE ε4/ε4 carriers.

KW - African

KW - Alzheimer's disease

KW - European

KW - ancestry

KW - apolipoprotein E ε4

KW - chromatin accessibility

KW - gene expression

KW - single nuclei assay for transposase accessible chromatin followed by sequencing

KW - single nucleus RNA sequencing

UR - http://www.scopus.com/inward/record.url?scp=85152687072&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85152687072&partnerID=8YFLogxK

U2 - 10.1002/alz.13075

DO - 10.1002/alz.13075

M3 - Article

C2 - 37037656

AN - SCOPUS:85152687072

SN - 1552-5260

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

ER -

Ancestry-related differences in chromatin accessibility and gene expression of APOE ε4 are associated with Alzheimer's disease risk

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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