Ancestry-related differences in chromatin accessibility and gene expression of APOE ε4 are associated with Alzheimer's disease risk
Katrina Celis
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorMaria D. M. Muniz Moreno
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorFarid Rajabli
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorPatrice Whitehead
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorKara Hamilton-Nelson
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorDerek M. Dykxhoorn
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorKaren Nuytemans
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorLiyong Wang
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorMargaret Flanagan
Northwestern ADC Neuropathology Core, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Search for more papers by this authorSandra Weintraub
Northwestern ADC Neuropathology Core, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Search for more papers by this authorChangiz Geula
Northwestern ADC Neuropathology Core, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Search for more papers by this authorMarla Gearing
Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, Georgia, USA
Search for more papers by this authorClifton L. Dalgard
The American Genome Center, Uniformed Services University, Bethesda, Maryland, USA
Collaborative Health Initiative Research Program, Henry Jackson Foundation, Bethesda, Maryland, USA
Department of Anatomy Physiology & Genetics, Uniformed Services University, Bethesda, Maryland, USA
Search for more papers by this authorFulai Jin
Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, USA
Search for more papers by this authorDavid A. Bennett
Department of Neurological Sciences, Rush University, Chicago, Illinois, USA
Search for more papers by this authorTheresa Schuck
The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
Search for more papers by this authorMargaret A. Pericak-Vance
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorAnthony J. Griswold
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorJuan I. Young
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorCorresponding Author
Jeffery M. Vance
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Correspondence
Jeffery M. Vance, University of Miami Miller School of Medicine, John P. Hussman Institute for Human Genomics, 1501 NW 10th Ave, BRB 509, Miami, FL 33136, USA.
Email: [email protected]
Search for more papers by this authorKatrina Celis
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorMaria D. M. Muniz Moreno
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorFarid Rajabli
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorPatrice Whitehead
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorKara Hamilton-Nelson
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorDerek M. Dykxhoorn
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorKaren Nuytemans
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorLiyong Wang
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorMargaret Flanagan
Northwestern ADC Neuropathology Core, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Search for more papers by this authorSandra Weintraub
Northwestern ADC Neuropathology Core, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Search for more papers by this authorChangiz Geula
Northwestern ADC Neuropathology Core, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Search for more papers by this authorMarla Gearing
Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, Georgia, USA
Search for more papers by this authorClifton L. Dalgard
The American Genome Center, Uniformed Services University, Bethesda, Maryland, USA
Collaborative Health Initiative Research Program, Henry Jackson Foundation, Bethesda, Maryland, USA
Department of Anatomy Physiology & Genetics, Uniformed Services University, Bethesda, Maryland, USA
Search for more papers by this authorFulai Jin
Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, USA
Search for more papers by this authorDavid A. Bennett
Department of Neurological Sciences, Rush University, Chicago, Illinois, USA
Search for more papers by this authorTheresa Schuck
The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
Search for more papers by this authorMargaret A. Pericak-Vance
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorAnthony J. Griswold
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorJuan I. Young
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorCorresponding Author
Jeffery M. Vance
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Correspondence
Jeffery M. Vance, University of Miami Miller School of Medicine, John P. Hussman Institute for Human Genomics, 1501 NW 10th Ave, BRB 509, Miami, FL 33136, USA.
Email: [email protected]
Search for more papers by this authorJuan I. Young and Jeffery M. Vance contributed equally.
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.
CONFLICTS OF INTEREST STATEMENT
K.C., M.D.M.M., F.R., P.W., K.H., D.M.D., K.N., L.W., M.F., S.W., C.G., M.G., C.L.D., F.J., D.A.B., T.S., M.A.P., A.J.G., J.I.Y., and J.M.V. have nothing to disclose. The authors declare that they have no competing interests. Author disclosures are available in the Supporting information.
Open Research
DATA AVAILABILITY STATEMENT
Data are available through the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) Data Sharing Service (DSS): https://dss.niagads.org/datasets/ng00067/
Supporting Information
| Filename | Description |
|---|---|
| alz13075-sup-0001-FiguresS1-S6.pdf5.7 MB | Supporting Information |
| alz13075-sup-0002-TablesS1-S7.docx336.2 KB | Supporting Information |
| alz13075-sup-0003-SuppMat.pdf2.9 MB | Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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