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Article ; Online: Nontargeted Plasma Proteomic Analysis of Renal Disease and Pulmonary Hypertension in Patients with Sickle Cell Disease.

Garrett, Melanie E / Foster, Matthew W / Telen, Marilyn J / Ashley-Koch, Allison E

2024 Volume 23, Issue 3, Page(s) 1039–1048

Abstract: Sickle cell disease (SCD) is characterized by red blood cell sickling, vaso-occlusion, hemolytic anemia, damage to multiple organ systems, and, as a result, shortened life expectancy. Sickle cell disease nephropathy (SCDN) and pulmonary hypertension ( ... ...

Abstract	Sickle cell disease (SCD) is characterized by red blood cell sickling, vaso-occlusion, hemolytic anemia, damage to multiple organ systems, and, as a result, shortened life expectancy. Sickle cell disease nephropathy (SCDN) and pulmonary hypertension (pHTN) are common and frequently co-occurring complications of SCD; both are associated with markedly accelerated mortality. To identify candidate circulating biomarkers of SCDN and pHTN, we used mass spectrometry to quantify the relative abundance of >1000 proteins in plasma samples from 189 adults with SCD from the Outcome Modifying Genes in SCD (OMG-SCD) cohort (ProteomeXchange identifier PXD048716). Forty-four proteins were differentially abundant in SCDN, most significantly cystatin-C and collagen α-1(XVIII) chain (COIA1), and 55 proteins were dysregulated in patients with SCDN and pHTN, most significantly insulin-like growth factor-binding protein 6 (IBP6). Network analysis identified a module of 133 coregulated proteins significantly associated with SCDN, that was enriched for extracellular matrix proteins, insulin-like growth factor binding proteins, cell adhesion proteins, EGF-like calcium binding proteins, and several cadherin family members. Collectively, these data provide a comprehensive understanding of plasma protein changes in SCDN and pHTN which validate numerous studies of chronic kidney disease and suggest shared profiles of protein disruption in kidney dysfunction and pHTN among SCD patients.
MeSH term(s)	Adult ; Humans ; Hypertension, Pulmonary/genetics ; Proteomics ; Anemia, Sickle Cell/complications ; Anemia, Sickle Cell/genetics ; Vascular Diseases ; Erythrocytes ; Collagen Type I
Chemical Substances	Collagen Type I
Language	English
Publishing date	2024-02-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.3c00748
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Article ; Online: Genome-wide DNA methylation analysis of cannabis use disorder in a veteran cohort enriched for posttraumatic stress disorder.

Garrett, Melanie E / Dennis, Michelle F / Bourassa, Kyle J / Hauser, Michael A / Kimbrel, Nathan A / Beckham, Jean C / Ashley-Koch, Allison E

Psychiatry research

2024 Volume 333, Page(s) 115757

Abstract: Cannabis use has been increasing over the past decade, not only in the general US population, but particularly among military veterans. With this rise in use has come a concomitant increase in cannabis use disorder (CUD) among veterans. Here, we ... ...

Abstract	Cannabis use has been increasing over the past decade, not only in the general US population, but particularly among military veterans. With this rise in use has come a concomitant increase in cannabis use disorder (CUD) among veterans. Here, we performed an epigenome-wide association study for lifetime CUD in an Iraq/Afghanistan era veteran cohort enriched for posttraumatic stress disorder (PTSD) comprising 2,310 total subjects (1,109 non-Hispanic black and 1,201 non-Hispanic white). We also investigated CUD interactions with current PTSD status and examined potential indirect effects of DNA methylation (DNAm) on the relationship between CUD and psychiatric diagnoses. Four CpGs were associated with lifetime CUD, even after controlling for the effects of current smoking (AHRR cg05575921, LINC00299 cg23079012, VWA7 cg22112841, and FAM70A cg08760398). Importantly, cg05575921, a CpG strongly linked to smoking, remained associated with lifetime CUD even when restricting the analysis to veterans who reported never smoking cigarettes. Moreover, CUD interacted with current PTSD to affect cg05575921 and cg23079012 such that those with both CUD and PTSD displayed significantly lower DNAm compared to the other groups. Finally, we provide preliminary evidence that AHRR cg05575921 helps explain the association between CUD and any psychiatric diagnoses, specifically mood disorders.
MeSH term(s)	Humans ; Stress Disorders, Post-Traumatic/epidemiology ; Stress Disorders, Post-Traumatic/genetics ; Stress Disorders, Post-Traumatic/psychology ; Veterans/psychology ; Marijuana Abuse/psychology ; DNA Methylation ; Substance-Related Disorders/epidemiology ; Cannabis
Language	English
Publishing date	2024-01-27
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	445361-x
ISSN	1872-7123 ; 1872-7506 ; 0925-4927 ; 0165-1781
ISSN (online)	1872-7123 ; 1872-7506
ISSN	0925-4927 ; 0165-1781
DOI	10.1016/j.psychres.2024.115757
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Article ; Online: Demographic characteristics and epigenetic biological aging among post-9/11 veterans: Associations of DunedinPACE with sex, race, and age.

Bourassa, Kyle J / Halverson, Tate F / Garrett, Melanie E / Hair, Lauren / Dennis, Michelle / Ashley-Koch, Allison E / Beckham, Jean C / Kimbrel, Nathan A

Psychiatry research

2024 Volume 336, Page(s) 115908

Abstract: Measures of epigenetic aging derived from DNA methylation (DNAm) have enabled the assessment of biological aging in new populations and cohorts. In the present study, we used an epigenetic measure of aging, DunedinPACE, to examine rates of aging across ... ...

Abstract	Measures of epigenetic aging derived from DNA methylation (DNAm) have enabled the assessment of biological aging in new populations and cohorts. In the present study, we used an epigenetic measure of aging, DunedinPACE, to examine rates of aging across demographic groups in a sample of 2,309 United States military veterans from the VISN 6 MIRECC's Post-Deployment Mental Health Study. As assessed by DunedinPACE, female veterans were aging faster than male veterans (β = 0.39, 95 % CI [0.29, 0.48], p < .001), non-Hispanic Black veterans were aging faster than non-Hispanic White veterans (β = 0.58, 95 % CI [0.50, 0.66], p < .001), and older veterans were biologically aging faster than younger veterans (β = 0.21, 95 % CI [0.18, 0.25], p < .001). In secondary analyses, these differences in rates of aging were not explained by a variety of biopsychosocial covariates. In addition, the percentage of European genetic admixture in non-Hispanic Black veterans was not associated with DunedinPACE. Our findings suggest that female and non-Hispanic Black veterans are at greater risk of accelerated aging among post-9/11 veterans. Interventions that slow aging might provide relatively greater benefit among veterans comprising these at-risk groups.
Language	English
Publishing date	2024-04-10
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	445361-x
ISSN	1872-7123 ; 1872-7506 ; 0925-4927 ; 0165-1781
ISSN (online)	1872-7123 ; 1872-7506
ISSN	0925-4927 ; 0165-1781
DOI	10.1016/j.psychres.2024.115908
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Article ; Online: Posttraumatic stress disorder, trauma, and accelerated biological aging among post-9/11 veterans.

Bourassa, Kyle J / Garrett, Melanie E / Caspi, Avshalom / Dennis, Michelle / Hall, Katherine S / Moffitt, Terrie E / Taylor, Gregory A / Ashley-Koch, Allison E / Beckham, Jean C / Kimbrel, Nathan A

Translational psychiatry

2024 Volume 14, Issue 1, Page(s) 4

Abstract: People who experience trauma and develop posttraumatic stress disorder (PTSD) are at increased risk for poor health. One mechanism that could explain this risk is accelerated biological aging, which is associated with the accumulation of chronic diseases, ...

Abstract	People who experience trauma and develop posttraumatic stress disorder (PTSD) are at increased risk for poor health. One mechanism that could explain this risk is accelerated biological aging, which is associated with the accumulation of chronic diseases, disability, and premature mortality. Using data from 2309 post-9/11 United States military veterans who participated in the VISN 6 MIRECC's Post-Deployment Mental Health Study, we tested whether PTSD and trauma exposure were associated with accelerated rate of biological aging, assessed using a validated DNA methylation (DNAm) measure of epigenetic aging-DunedinPACE. Veterans with current PTSD were aging faster than those who did not have current PTSD, β = 0.18, 95% CI [0.11, 0.27], p < .001. This effect represented an additional 0.4 months of biological aging each year. Veterans were also aging faster if they reported more PTSD symptoms, β = 0.13, 95% CI [0.09, 0.16], p < 0.001, or higher levels of trauma exposure, β = 0.09, 95% CI [0.05, 0.13], p < 0.001. Notably, veterans with past PTSD were aging more slowly than those with current PTSD, β = -0.21, 95% CI [-0.35, -0.07], p = .003. All reported results accounted for age, gender, self-reported race/ethnicity, and education, and remained when controlling for smoking. Our findings suggest that an accelerated rate of biological aging could help explain how PTSD contributes to poor health and highlights the potential benefits of providing efficacious treatment to populations at increased risk of trauma and PTSD.
MeSH term(s)	Humans ; Stress Disorders, Post-Traumatic/epidemiology ; Veterans ; Aging ; DNA Methylation ; Educational Status
Language	English
Publishing date	2024-01-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-023-02704-y
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Article ; Online: Epigenetic Aging Associations With Psychoneurological Symptoms and Social Functioning in Adults With Sickle Cell Disease.

Knisely, Mitchell R / Masese, Rita V / Mathias, Joacy G / Yang, Qing / Hatch, Daniel / Lê, Brandon M / Luyster, Faith / Garrett, Melanie E / Tanabe, Paula J / Shah, Nirmish R / Ashley-Koch, Allison

Biological research for nursing

2024 , Page(s) 10998004241250322

Abstract: Objective: ...

Abstract	Objective:
Language	English
Publishing date	2024-04-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2145107-2
ISSN	1552-4175 ; 1099-8004
ISSN (online)	1552-4175
ISSN	1099-8004
DOI	10.1177/10998004241250322
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Article ; Online: Deployment-related toxic exposures are associated with worsening mental and physical health after military service: Results from a self-report screening of veterans deployed after 9/11.

Bourassa, Kyle J / Wagner, H Ryan / Halverson, Tate F / Ashley-Koch, Allison E / Beckham, Jean / Garrett, Melanie E / Kimbrel, Nathan A / Naylor, Jennifer C

Journal of psychiatric research

2024 Volume 174, Page(s) 283–288

Abstract: Exposure to toxins-such as heavy metals and air pollution-can result in poor health and wellbeing. Recent scientific and media attention has highlighted negative health outcomes associated with toxic exposures for U.S. military personnel deployed ... ...

Abstract	Exposure to toxins-such as heavy metals and air pollution-can result in poor health and wellbeing. Recent scientific and media attention has highlighted negative health outcomes associated with toxic exposures for U.S. military personnel deployed overseas. Despite established health risks, less empirical work has examined whether deployment-related toxic exposures are associated with declines in mental and physical health after leaving military service, particularly among the most recent cohort of veterans deployed after September 11, 2001. Using data from 659 U.S. veterans in the VISN 6 MIRECC Post-Deployment Mental Health Study, we tested whether self-reported toxic exposures were associated with poorer mental and physical health. At baseline, veterans who reported more toxic exposures also reported more mental health, β = 0.14, 95% CI [0.04, 0.23], p = 0.004, and physical health symptoms, β = 0.21, 95% CI [0.11, 0.30], p < 0.001. Over the next ten years, veterans reporting more toxic exposures also had greater increases in mental health symptoms, β = 0.23, 95% CI [0.15, 0.31], p < 0.001, physical health symptoms, β = 0.22, 95% CI [0.14, 0.30], p < 0.001, and chronic disease diagnoses, β = 0.15, 95% CI [0.07, 0.23], p < 0.001. These associations accounted for demographic and military covariates, including combat exposure. Our findings suggest that toxic exposures are associated with worsening mental and physical health after military service, and this recent cohort of veterans will have increased need for mental health and medical care as they age into midlife and older age.
Language	English
Publishing date	2024-04-23
Publishing country	England
Document type	Journal Article
ZDB-ID	3148-3
ISSN	1879-1379 ; 0022-3956
ISSN (online)	1879-1379
ISSN	0022-3956
DOI	10.1016/j.jpsychires.2024.04.043
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Article ; Online: Impact of traumatic life events and polygenic risk scores for major depression and posttraumatic stress disorder on Iraq/Afghanistan Veterans.

Lipsky, Rachele K / Garrett, Melanie E / Dennis, Michelle F / Hauser, Michael A / Beckham, Jean C / Ashley-Koch, Allison E / Kimbrel, Nathan A

Journal of psychiatric research

2022 Volume 158, Page(s) 15–19

Abstract: Traumatic experiences and genetic heritability are among the most widely acknowledged risk factors leading to the development of psychopathology; including posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). The purpose of this ... ...

Abstract	Traumatic experiences and genetic heritability are among the most widely acknowledged risk factors leading to the development of psychopathology; including posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). The purpose of this study was to investigate if polygenic risk scores (PRS) among Veterans interacted with traumatic stress to predict PTSD and MDD. 1,389 Iraq-Afghanistan military service Veterans from the Mental Illness Research Education and Clinical Center dataset were analyzed. Genome-wide association study (GWAS) statistics were utilized to generate PRS for PTSD (PRS
MeSH term(s)	Humans ; Veterans ; Depressive Disorder, Major/epidemiology ; Depressive Disorder, Major/genetics ; Depressive Disorder, Major/complications ; Stress Disorders, Post-Traumatic/epidemiology ; Stress Disorders, Post-Traumatic/genetics ; Stress Disorders, Post-Traumatic/complications ; Depression ; Afghanistan ; Iraq ; Genome-Wide Association Study ; Risk Factors
Language	English
Publishing date	2022-12-16
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3148-3
ISSN	1879-1379 ; 0022-3956
ISSN (online)	1879-1379
ISSN	0022-3956
DOI	10.1016/j.jpsychires.2022.12.014
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Article ; Online: Characterizing epigenetic aging in an adult sickle cell disease cohort.

Lê, Brandon M / Hatch, Daniel / Yang, Qing / Shah, Nirmish / Luyster, Faith S / Garrett, Melanie E / Tanabe, Paula / Ashley-Koch, Allison E / Knisely, Mitchell R

Blood advances

2023 Volume 8, Issue 1, Page(s) 47–55

Abstract: Abstract: Sickle cell disease (SCD) affects ∼100 000 predominantly African American individuals in the United States, causing significant cellular damage, increased disease complications, and premature death. However, the contribution of epigenetic ... ...

Abstract	Abstract: Sickle cell disease (SCD) affects ∼100 000 predominantly African American individuals in the United States, causing significant cellular damage, increased disease complications, and premature death. However, the contribution of epigenetic factors to SCD pathophysiology remains relatively unexplored. DNA methylation (DNAm), a primary epigenetic mechanism for regulating gene expression in response to the environment, is an important driver of normal cellular aging. Several DNAm epigenetic clocks have been developed to serve as a proxy for cellular aging. We calculated the epigenetic ages of 89 adults with SCD (mean age, 30.64 years; 60.64% female) using 5 published epigenetic clocks: Horvath, Hannum, PhenoAge, GrimAge, and DunedinPACE. We hypothesized that in chronic disease, such as SCD, individuals would demonstrate epigenetic age acceleration, but the results differed depending on the clock used. Recently developed clocks more consistently demonstrated acceleration (GrimAge, DunedinPACE). Additional demographic and clinical phenotypes were analyzed to explore their association with epigenetic age estimates. Chronological age was significantly correlated with epigenetic age in all clocks (Horvath, r = 0.88; Hannum, r = 0.89; PhenoAge, r = 0.85; GrimAge, r = 0.88; DunedinPACE, r = 0.34). The SCD genotype was associated with 2 clocks (PhenoAge, P = .02; DunedinPACE, P < .001). Genetic ancestry, biological sex, β-globin haplotypes, BCL11A rs11886868, and SCD severity were not associated. These findings, among the first to interrogate epigenetic aging in adults with SCD, demonstrate epigenetic age acceleration with recently developed epigenetic clocks but not older-generation clocks. Further development of epigenetic clocks may improve their predictive ability and utility for chronic diseases such as SCD.
MeSH term(s)	Adult ; Humans ; Female ; Male ; Aging/genetics ; Cellular Senescence ; Anemia, Sickle Cell/genetics ; Black or African American/genetics ; Epigenesis, Genetic
Language	English
Publishing date	2023-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023011188
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Article: Large epigenome-wide association study identifies multiple novel differentially methylated CpG sites associated with suicidal thoughts and behaviors in veterans.

Kimbrel, Nathan A / Garrett, Melanie E / Evans, Mariah K / Mellows, Clara / Dennis, Michelle F / Hair, Lauren P / Hauser, Michael A / Ashley-Koch, Allison E / Beckham, Jean C

Frontiers in psychiatry

2023 Volume 14, Page(s) 1145375

Abstract: Introduction: The U.S. suicide mortality rate has steadily increased during the past two decades, particularly among military veterans; however, the epigenetic basis of suicidal thoughts and behaviors (STB) remains largely unknown.: Methods: To ... ...

Abstract	Introduction: The U.S. suicide mortality rate has steadily increased during the past two decades, particularly among military veterans; however, the epigenetic basis of suicidal thoughts and behaviors (STB) remains largely unknown. Methods: To address this issue, we conducted an epigenome-wide association study of DNA methylation (DNAm) of peripheral blood samples obtained from 2,712 U.S. military veterans. Results: Three DNAm probes were significantly associated with suicide attempts, surpassing the multiple testing threshold (FDR Discussion: Taken together, the present findings suggest that
Language	English
Publishing date	2023-05-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564218-2
ISSN	1664-0640
ISSN	1664-0640
DOI	10.3389/fpsyt.2023.1145375
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Article: Integrative single-nucleus multi-omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer's disease brains.

Gamache, Julia / Gingerich, Daniel / Shwab, E Keats / Barrera, Julio / Garrett, Melanie E / Hume, Cordelia / Crawford, Gregory E / Ashley-Koch, Allison E / Chiba-Falek, Ornit

Cell & bioscience

2023 Volume 13, Issue 1, Page(s) 185

Abstract: Background: The genetic underpinnings of late-onset Alzheimer's disease (LOAD) are yet to be fully elucidated. Although numerous LOAD-associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since the ... ...

Abstract	Background: The genetic underpinnings of late-onset Alzheimer's disease (LOAD) are yet to be fully elucidated. Although numerous LOAD-associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since the brain is composed of heterogenous cell subtypes, it is imperative to study the brain on a cell subtype specific level to explore the biological processes underlying LOAD. Methods: Here, we present the largest parallel single-nucleus (sn) multi-omics study to simultaneously profile gene expression (snRNA-seq) and chromatin accessibility (snATAC-seq) to date, using nuclei from 12 normal and 12 LOAD brains. We identified cell subtype clusters based on gene expression and chromatin accessibility profiles and characterized cell subtype-specific LOAD-associated differentially expressed genes (DEGs), differentially accessible peaks (DAPs) and cis co-accessibility networks (CCANs). Results: Integrative analysis defined disease-relevant CCANs in multiple cell subtypes and discovered LOAD-associated cell subtype-specific candidate cis regulatory elements (cCREs), their candidate target genes, and trans-interacting transcription factors (TFs), some of which, including ELK1, JUN, and SMAD4 in excitatory neurons, were also LOAD-DEGs. Finally, we focused on a subset of cell subtype-specific CCANs that overlap known LOAD-GWAS regions and catalogued putative functional SNPs changing the affinities of TF motifs within LOAD-cCREs linked to LOAD-DEGs, including APOE and MYO1E in a specific subtype of microglia and BIN1 in a subpopulation of oligodendrocytes. Conclusions: To our knowledge, this study represents the most comprehensive systematic interrogation to date of regulatory networks and the impact of genetic variants on gene dysregulation in LOAD at a cell subtype resolution. Our findings reveal crosstalk between epigenetic, genomic, and transcriptomic determinants of LOAD pathogenesis and define catalogues of candidate genes, cCREs, and variants involved in LOAD genetic etiology and the cell subtypes in which they act to exert their pathogenic effects. Overall, these results suggest that cell subtype-specific cis-trans interactions between regulatory elements and TFs, and the genes dysregulated by these networks contribute to the development of LOAD.
Language	English
Publishing date	2023-10-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2593367-X
ISSN	2045-3701
ISSN	2045-3701
DOI	10.1186/s13578-023-01120-5
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