Harnessing chromatin loops to identify susceptibility genes in different populations for Alzheimer’s disease: rs3851179 links to PICALM not EED Article Swipe
Liyong Wang
,
Wanying Xu
,
Farid Rajabli
,
Katrina Celis
,
Leina Lu
,
Marla Gearing
,
David A. Bennett
,
Margaret E. Flanagan
,
Sandra Weıntraub
,
Changiz Geula
,
Theresa Schuck
,
William K. Scott
,
Derek M. Dykxhoorn
,
Anthony J. Griswold
,
Margaret A. Pericak‐Vance
,
Juan I. Young
,
Fulai Jin
,
Jeffery M. Vance
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1002/alz.092337
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1002/alz.092337
Background Annotation of target genes of non‐coding GWAS loci remains a challenge since 1) regulatory elements identified by GWAS can be metabases away from its actual target, 2) one regulatory element can target multiple genes, and 3) multiple regulatory elements can target one gene. AD GWAS in populations with different ancestries have identified different loci, suggesting ancestry‐specific genetic risks. To understand the connection between associated loci (potential regulatory elements) and their target genes, we conducted Hi‐C analysis in frontal cortex of African American (AA) and Non‐Hispanic Whites (NHW) AD patients to map chromatin loops, which often represent enhancer‐promoter (EP) interactions. In our initial analyses, we applied HiC to uncover the regulatory architecture of rs3851179 linked to the embryonic ectoderm development gene ( EED ) in the ADSP gene verification list. Method Hi‐C libraries were derived from four AA and four NHW donors matched for age, sex, and APOE genotype. The AA samples had 68∼88% African (AF) genome while NHW samples had >95% European (EU) genome. DeepLoop was used to generate robust maps of chromatin loops. Hi‐C data from each population were pooled to generate reference chromatin loop maps for the AF and EU genomes. Result rs3851179 (OR = 0.9, P = 3.0 × 10 −48 ) resides between EED and PICALM , about 80 Kb away from both with each gene transcribed in opposite directions. Although PICALM is designated as a causal gene, EED is designated a susceptibility gene by ADSP based on the transcription direction and distance from rs3851179. Hi‐C data from both AF and EU genome in frontal cortex revealed that rs3851179 co‐localizes with a loop anchor, connecting H3K27ac peaks (enhancer) overlapping rs3851179 to the proximal promoter of PICALM , suggesting that PICALM but not EED is the target gene, corroborated by the GTEX e‐QTL data. Conclusion This initial application of Hi‐C data demonstrates the utility of chromatin regulatory maps in nominating target genes of GWAS hits in non‐coding loci. The generation and eventual application of Hi‐C maps in African and Amerindian genomes (which are part of the AA or American Hispanic genomic admixture) will be key dissecting ancestry‐specific genetic loci and, thereby, broadening diversity in AD research.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1002/alz.092337
- OA Status
- hybrid
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4406049410
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4406049410Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1002/alz.092337Digital Object Identifier
- Title
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Harnessing chromatin loops to identify susceptibility genes in different populations for Alzheimer’s disease: rs3851179 links to PICALM not EEDWork title
- Type
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articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2024Year of publication
- Publication date
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2024-12-01Full publication date if available
- Authors
-
Liyong Wang, Wanying Xu, Farid Rajabli, Katrina Celis, Leina Lu, Marla Gearing, David A. Bennett, Margaret E. Flanagan, Sandra Weıntraub, Changiz Geula, Theresa Schuck, William K. Scott, Derek M. Dykxhoorn, Anthony J. Griswold, Margaret A. Pericak‐Vance, Juan I. Young, Fulai Jin, Jeffery M. VanceList of authors in order
- Landing page
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https://doi.org/10.1002/alz.092337Publisher landing page
- Open access
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YesWhether a free full text is available
- OA status
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hybridOpen access status per OpenAlex
- OA URL
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https://doi.org/10.1002/alz.092337Direct OA link when available
- Concepts
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Genetics, Chromatin, Biology, Disease, Gene, Computational biology, Medicine, PathologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
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10Other works algorithmically related by OpenAlex
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| publication_date | 2024-12-01 |
| publication_year | 2024 |
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