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Article ; Online: Deconstructing the epigenomic architecture of human neurodegeneration.

De Jager, Philip L

2021 Volume 153, Page(s) 105331

Abstract: The past 10 years have seen a rapid advance in our ability to profile the epigenome from human pathologic material, opening up new study designs to investigate the role of epigenomic features in human disease. Moderate to large scale studies have now ... ...

Abstract	The past 10 years have seen a rapid advance in our ability to profile the epigenome from human pathologic material, opening up new study designs to investigate the role of epigenomic features in human disease. Moderate to large scale studies have now been conducted in the target tissue of neurodegenerative diseases, the brain, and, through the use of rigorous statistical methodologies, have laid a foundation of validated observations and successful study designs that inform our perspective on the role of the epigenome in these diseases, generate new hypotheses, and guide our path forward for a second generation of studies. It is clear that sampling the epigenome is not redundant with other "omic" profiling of the same tissue and that it can serve as an important vehicle for the integration of the effect of multiple environmental exposures on risk of disease. In some cases, change in the epigenome may thus have a causal impact on disease, but we now have evidence that such changes may also mediate some of the effect of tau proteinopathy and that other changes may moderate the impact of genetic risk factors. Thus, the epigenome may be involved at multiple different stages of the sequence of events that leads to human neurodegeneration, and we review the study designs that may begin to guide the development of a more comprehensive perspective on the aging brain's epigenome.
MeSH term(s)	Brain/metabolism ; Epigenome/genetics ; Epigenomics ; Humans ; Neurodegenerative Diseases/genetics ; Tauopathies/genetics
Language	English
Publishing date	2021-03-09
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2021.105331
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Article ; Online: Neuroimmune contributions to Alzheimer's disease: a focus on human data.

Haage, Verena / De Jager, Philip L

Molecular psychiatry

2022 Volume 27, Issue 8, Page(s) 3164–3181

Abstract: The past decade has seen the convergence of a series of new insights that arose from genetic and systems analyses of Alzheimer's disease (AD) with a wealth of epidemiological data from a variety of fields; this resulted in renewed interest in immune ... ...

Abstract	The past decade has seen the convergence of a series of new insights that arose from genetic and systems analyses of Alzheimer's disease (AD) with a wealth of epidemiological data from a variety of fields; this resulted in renewed interest in immune responses as important, potentially causal components of AD. Here, we focus primarily on a review of human data which has recently yielded a set of robust, reproducible results that exist in a much larger universe of conflicting reports stemming from small studies with important limitations in their study design. Thus, we are at an important crossroads in efforts to first understand at which step of the long, multiphasic course of AD a given immune response may play a causal role and then modulate this response to slow or block the pathophysiology of AD. We have a wealth of new experimental tools, analysis methods, and capacity to sample human participants at large scale longitudinally; these resources, when coupled to a foundation of reproducible results and novel study designs, will enable us to monitor human immune function in the CNS at the level of complexity that is required while simultaneously capturing the state of the peripheral immune system. This integration of peripheral and central perturbations in immune responses results in pathologic responses in the central nervous system parenchyma where specialized cellular microenvironments composed of multiple cell subtypes respond to these immune perturbations as well as to environmental exposures, comorbidities and the impact of the advancing life course. Here, we offer an overview that seeks to illustrate the large number of interconnecting factors that ultimately yield the neuroimmune component of AD.
MeSH term(s)	Humans ; Alzheimer Disease/pathology ; Central Nervous System ; Causality ; Research Design
Language	English
Publishing date	2022-06-06
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1330655-8
ISSN	1476-5578 ; 1359-4184
ISSN (online)	1476-5578
ISSN	1359-4184
DOI	10.1038/s41380-022-01637-0
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Article ; Online: Is the goal of an epigenomic study to determine causality?

De Jager, Philip L

Multiple sclerosis (Houndmills, Basingstoke, England)

2018 Volume 24, Issue 7, Page(s) 908–909

MeSH term(s)	Epigenomics/methods ; Humans ; Multiple Sclerosis/genetics
Language	English
Publishing date	2018-07-03
Publishing country	England
Document type	Journal Article
ZDB-ID	1290669-4
ISSN	1477-0970 ; 1352-4585
ISSN (online)	1477-0970
ISSN	1352-4585
DOI	10.1177/1352458517750771
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Article: Genetic insights into the association between inflammatory bowel disease and Alzheimer's disease.

Zeng, Lu / White, Charles C / Bennett, David A / Klein, Hans-Ulrich / De Jager, Philip L

medRxiv : the preprint server for health sciences

2023

Abstract: Background: Myeloid cells, including monocytes, macrophages, microglia, dendritic cells and neutrophils are a part of innate immunity, playing a major role in orchestrating innate and adaptive immune responses. Microglia are the resident myeloid cells ... ...

Abstract	Background: Myeloid cells, including monocytes, macrophages, microglia, dendritic cells and neutrophils are a part of innate immunity, playing a major role in orchestrating innate and adaptive immune responses. Microglia are the resident myeloid cells of the central nervous system, and many Alzheimer's disease (AD) risk loci are found in or near genes that are highly or sometimes uniquely expressed in myeloid cells. Similarly, inflammatory bowel disease (IBD) loci are also enriched for genes expressed by myeloid cells. However, the extent to which there is overlap between the effects of AD and IBD susceptibility loci in myeloid cells remains poorly described, and the substantial IBD genetic maps may help to accelerate AD research. Methods: Here, we leveraged summary statistics from large-scale genome-wide association studies (GWAS) to investigate the causal effect of IBD (including ulcerative colitis and Crohn's disease) variants on AD and AD endophenotypes. Microglia and monocyte expression Quantitative Trait Locus (eQTLs) were used to examine the functional consequences of IBD and AD risk variants enrichment in two different myeloid cell subtypes. Results: Our results showed that, while Conclusion: To our knowledge, this is the first study to systematically contrast the genetic association between IBD and AD, our findings highlight a possible genetically protective effect of IBD on AD even if the majority of effects on myeloid cell gene expression by the two sets of disease variants are distinct. Thus, IBD myeloid studies may not help to accelerate AD functional studies, but our observation reinforces the role of myeloid cells in the accumulation of tau proteinopathy and provides a new avenue for discovering a protective factor.
Language	English
Publishing date	2023-04-17
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.17.23286845
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Article ; Online: The era of GWAS is over - No.

De Jager, Philip L

Multiple sclerosis (Houndmills, Basingstoke, England)

2017 Volume 24, Issue 3, Page(s) 258–260

MeSH term(s)	Genome-Wide Association Study/trends ; Humans ; Multiple Sclerosis/genetics
Language	English
Publishing date	2017-12-18
Publishing country	England
Document type	Journal Article
ZDB-ID	1290669-4
ISSN	1477-0970 ; 1352-4585
ISSN (online)	1477-0970
ISSN	1352-4585
DOI	10.1177/1352458517742980
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Article ; Online: Association of whole-person eigen-polygenic risk scores with Alzheimer's disease.

Kharaghani, Amin / Tio, Earvin S / Milic, Milos / Bennett, David A / De Jager, Philip L / Schneider, Julie A / Sun, Lei / Felsky, Daniel

Human molecular genetics

2024

Abstract: Late-Onset Alzheimer's Disease (LOAD) is a heterogeneous neurodegenerative disorder with complex etiology and high heritability. Its multifactorial risk profile and large portions of unexplained heritability suggest the involvement of yet unidentified ... ...

Abstract	Late-Onset Alzheimer's Disease (LOAD) is a heterogeneous neurodegenerative disorder with complex etiology and high heritability. Its multifactorial risk profile and large portions of unexplained heritability suggest the involvement of yet unidentified genetic risk factors. Here we describe the "whole person" genetic risk landscape of polygenic risk scores for 2218 traits in 2044 elderly individuals and test if novel eigen-PRSs derived from clustered subnetworks of single-trait PRSs can improve the prediction of LOAD diagnosis, rates of cognitive decline, and canonical LOAD neuropathology. Network analyses revealed distinct clusters of PRSs with clinical and biological interpretability. Novel eigen-PRSs (ePRS) from these clusters significantly improved LOAD-related phenotypes prediction over current state-of-the-art LOAD PRS models. Notably, an ePRS representing clusters of traits related to cholesterol levels was able to improve variance explained in a model of the brain-wide beta-amyloid burden by 1.7% (likelihood ratio test P = 9.02 × 10-7). All associations of ePRS with LOAD phenotypes were eliminated by the removal of APOE-proximal loci. However, our association analysis identified modules characterized by PRSs of high cholesterol and LOAD. We believe this is due to the influence of the APOE region from both PRSs. We found significantly higher mean SNP effects for LOAD in the intersecting APOE region SNPs. Combining genetic risk factors for vascular traits and dementia could improve current single-trait PRS models of LOAD, enhancing the use of PRS in risk stratification. Our results are catalogued for the scientific community, to aid in generating new hypotheses based on our maps of clustered PRSs and associations with LOAD-related phenotypes.
Language	English
Publishing date	2024-04-27
Publishing country	England
Document type	Journal Article
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddae067
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Article ; Online: Genetic and gene expression signatures in multiple sclerosis.

Patsopoulos, Nikolaos A / De Jager, Philip L

Multiple sclerosis (Houndmills, Basingstoke, England)

2020 Volume 26, Issue 5, Page(s) 576–581

Abstract: Multiple sclerosis (MS) exhibits a well-documented increased incidence in individuals with respective family history, that is, is a heritable disease. In the last decade, genome-wide association studies have enabled the agnostic interrogation of the ... ...

Abstract	Multiple sclerosis (MS) exhibits a well-documented increased incidence in individuals with respective family history, that is, is a heritable disease. In the last decade, genome-wide association studies have enabled the agnostic interrogation of the whole genome at a large scale. To date, over 200 genetic associations have been described at the strict level of genome-wide significance. Our current understanding of MS genetics can explain up to half of the disease's heritability, raising the important question of whether this is enough information to leverage toward improving diagnosis in MS. Parallel advancements in technologies that allow the characterization of the full transcriptome down to the single-cell level have enabled the generation of an unprecedented wealth of information. Transcriptional changes of putative causal cells could be utilized to identify early signs of disease onset. These recent findings in genetics and genomics, coupled with new technologies and deeply phenotyped cohorts, have the potential to improve the diagnosis of MS.
MeSH term(s)	Gene Expression/genetics ; Gene Expression Profiling ; Genetic Predisposition to Disease/genetics ; Humans ; Multiple Sclerosis/genetics
Language	English
Publishing date	2020-01-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1290669-4
ISSN	1477-0970 ; 1352-4585
ISSN (online)	1477-0970
ISSN	1352-4585
DOI	10.1177/1352458519898332
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Article ; Online: Considerations for integrative multi-omic approaches to explore Alzheimer's disease mechanisms.

Ma, Yiyi / Klein, Hans-Ulrich / De Jager, Philip L

Brain pathology (Zurich, Switzerland)

2020 Volume 30, Issue 5, Page(s) 984–991

Abstract: The past decade has seen the maturation of multiple different forms of high-dimensional molecular profiling to the point that these methods could be deployed in initially hundreds and more recently thousands of human samples. In the field of Alzheimer's ... ...

Abstract	The past decade has seen the maturation of multiple different forms of high-dimensional molecular profiling to the point that these methods could be deployed in initially hundreds and more recently thousands of human samples. In the field of Alzheimer's disease (AD), these profiles have been applied to the target organ: the aging brain. In a growing number of cases, the same samples were profiled with multiple different approaches, yielding genetic, transcriptomic, epigenomic and proteomic data. Here, we review lessons learned so far as we move beyond quantitative trait locus (QTL) analyses which map the effect of genetic variation on molecular features to integrate multiple levels of "omic" data in an effort to identify the molecular drivers of AD. One thing is clear: no single layer of molecular or "omic" data is sufficient to capture the variance of AD or aging-related cognitive decline. Nonetheless, reproducible findings are emerging from current efforts, and there is evidence of convergence using different approaches. Thus, we are on the cusp of an acceleration of truly integrative studies as the availability of large numbers of well-characterized brain samples profiled in three or more dimensions enables the testing, comparison and refinement of analytic methods with which to dissect the molecular architecture of the aging brain.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Cognitive Dysfunction/genetics ; Computational Biology/methods ; Epigenesis, Genetic/genetics ; Epigenomics/methods ; Gene Expression Profiling/methods ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study/methods ; Genomics/methods ; Humans ; Neurodegenerative Diseases/genetics ; Proteomics/methods
Language	English
Publishing date	2020-08-04
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1051484-3
ISSN	1750-3639 ; 1015-6305
ISSN (online)	1750-3639
ISSN	1015-6305
DOI	10.1111/bpa.12878
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Article ; Online: Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer's Disease.

Cosacak, Mehmet Ilyas / Bhattarai, Prabesh / De Jager, Philip L / Menon, Vilas / Tosto, Giuseppe / Kizil, Caghan

Cells

2022 Volume 11, Issue 11

Abstract: Neurogenesis is significantly reduced in Alzheimer's disease (AD) and is a potential therapeutic target. Contrary to humans, a zebrafish can regenerate its diseased brain, and thus is ideal for studying neurogenesis. To compare the AD-related molecular ... ...

Abstract	Neurogenesis is significantly reduced in Alzheimer's disease (AD) and is a potential therapeutic target. Contrary to humans, a zebrafish can regenerate its diseased brain, and thus is ideal for studying neurogenesis. To compare the AD-related molecular pathways between humans and zebrafish, we compared single cell or nuclear transcriptomic data from a zebrafish amyloid toxicity model and its controls (N = 12) with the datasets of two human adult brains (N = 10 and N = 48 (Microglia)), and one fetal brain (N = 10). Approximately 95.4% of the human and zebrafish cells co-clustered. Within each cell type, we identified differentially expressed genes (DEGs), enriched KEGG pathways, and gene ontology terms. We studied synergistic and non-synergistic DEGs to point at either common or uniquely altered mechanisms across species. Using the top DEGs, a high concordance in gene expression changes between species was observed in neuronal clusters. On the other hand, the molecular pathways affected by AD in zebrafish astroglia differed from humans in favor of the neurogenic pathways. The integration of zebrafish and human transcriptomes shows that the zebrafish can be used as a tool to study the cellular response to amyloid proteinopathies. Uniquely altered pathways in zebrafish could highlight the specific mechanisms underlying neurogenesis, which are absent in humans, and could serve as potential candidates for therapeutic developments.
MeSH term(s)	Alzheimer Disease/genetics ; Animals ; Humans ; Neurogenesis/genetics ; Solitary Nucleus ; Transcriptome/genetics ; Zebrafish/genetics
Language	English
Publishing date	2022-05-31
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11111807
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Article ; Online: Multi-omic integration via similarity network fusion to detect molecular subtypes of ageing.

Yang, Mu / Matan-Lithwick, Stuart / Wang, Yanling / De Jager, Philip L / Bennett, David A / Felsky, Daniel

Brain communications

2023 Volume 5, Issue 2, Page(s) fcad110

Abstract: Molecular subtyping of brain tissue provides insights into the heterogeneity of common neurodegenerative conditions, such as Alzheimer's disease. However, existing subtyping studies have mostly focused on single data modalities and only those individuals ...

Abstract	Molecular subtyping of brain tissue provides insights into the heterogeneity of common neurodegenerative conditions, such as Alzheimer's disease. However, existing subtyping studies have mostly focused on single data modalities and only those individuals with severe cognitive impairment. To address these gaps, we applied similarity network fusion, a method capable of integrating multiple high-dimensional multi-omic data modalities simultaneously, to an elderly sample spanning the full spectrum of cognitive ageing trajectories. We analyzed human frontal cortex brain samples characterized by five omic modalities: bulk RNA sequencing (18 629 genes), DNA methylation (53 932 CpG sites), histone acetylation (26 384 peaks), proteomics (7737 proteins) and metabolomics (654 metabolites). Similarity network fusion followed by spectral clustering was used for subtype detection, and subtype numbers were determined by Eigen-gap and rotation cost statistics. Normalized mutual information determined the relative contribution of each modality to the fused network. Subtypes were characterized by associations with 13 age-related neuropathologies and cognitive decline. Fusion of all five data modalities (
Language	English
Publishing date	2023-04-04
Publishing country	England
Document type	Journal Article
ISSN	2632-1297
ISSN (online)	2632-1297
DOI	10.1093/braincomms/fcad110
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