scholarly journals Summary-Based Methylome-Wide Association Analyses Suggest Potential Genetically Driven Epigenetic Heterogeneity of Alzheimer’s Disease

2020 ◽  
Vol 9 (5) ◽  
pp. 1489
Author(s):  
Alireza Nazarian ◽  
Anatoliy I. Yashin ◽  
Alexander M. Kulminski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Tissue Samples ◽  
Significance Level ◽  
Association Analyses ◽  
Functional Studies ◽  
Genome Wide ◽  
Summary Data

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no curative treatment available. Exploring the genetic and non-genetic contributors to AD pathogenesis is essential to better understand its underlying biological mechanisms, and to develop novel preventive and therapeutic strategies. We investigated potential genetically driven epigenetic heterogeneity of AD through summary data-based Mendelian randomization (SMR), which combined results from our previous genome-wide association analyses with those from two publicly available methylation quantitative trait loci studies of blood and brain tissue samples. We found that 152 probes corresponding to 113 genes were epigenetically associated with AD at a Bonferroni-adjusted significance level of 5.49E-07. Of these, 10 genes had significant probes in both brain-specific and blood-based analyses. Comparing males vs. females and hypertensive vs. non-hypertensive subjects, we found that 22 and 79 probes had group-specific associations with AD, respectively, suggesting a potential role for such epigenetic modifications in the heterogeneous nature of AD. Our analyses provided stronger evidence for possible roles of four genes (i.e., AIM2, C16orf80, DGUOK, and ST14) in AD pathogenesis as they were also transcriptionally associated with AD. The identified associations suggest a list of prioritized genes for follow-up functional studies and advance our understanding of AD pathogenesis.

scholarly journals Topological Dissection of Proteomic Changes Linked to the Limbic Stage of Alzheimer’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Erika Velásquez ◽  
Beáta Szeitz ◽  
Jeovanis Gil ◽  
Jimmy Rodriguez ◽  
Miklós Palkovits ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Brain Area ◽  
Disease Classification ◽  
Molecular Heterogeneity ◽  
Braak Stage ◽  
Tissue Samples ◽  
Major Player

Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common cause of dementia worldwide. In AD, neurodegeneration spreads throughout different areas of the central nervous system (CNS) in a gradual and predictable pattern, causing progressive memory decline and cognitive impairment. Deposition of neurofibrillary tangles (NFTs) in specific CNS regions correlates with the severity of AD and constitutes the basis for disease classification into different Braak stages (I-VI). Early clinical symptoms are typically associated with stages III-IV (i.e., limbic stages) when the involvement of the hippocampus begins. Histopathological changes in AD have been linked to brain proteome alterations, including aberrant posttranslational modifications (PTMs) such as the hyperphosphorylation of Tau. Most proteomic studies to date have focused on AD progression across different stages of the disease, by targeting one specific brain area at a time. However, in AD vulnerable regions, stage-specific proteomic alterations, including changes in PTM status occur in parallel and remain poorly characterized. Here, we conducted proteomic, phosphoproteomic, and acetylomic analyses of human postmortem tissue samples from AD (Braak stage III-IV, n=11) and control brains (n=12), covering all anatomical areas affected during the limbic stage of the disease (total hippocampus, CA1, entorhinal and perirhinal cortices). Overall, ~6000 proteins, ~9000 unique phosphopeptides and 221 acetylated peptides were accurately quantified across all tissues. Our results reveal significant proteome changes in AD brains compared to controls. Among others, we have observed the dysregulation of pathways related to the adaptive and innate immune responses, including several altered antimicrobial peptides (AMPs). Notably, some of these changes were restricted to specific anatomical areas, while others altered according to disease progression across the regions studied. Our data highlights the molecular heterogeneity of AD and the relevance of neuroinflammation as a major player in AD pathology. Data are available via ProteomeXchange with identifier PXD027173.

scholarly journals Follow-Up Study of Susceptibility Loci for Alzheimer's Disease and Onset Age Identified by Genome-Wide Association

2010 ◽  
Vol 19 (4) ◽  
pp. 1169-1175 ◽  
Author(s):  
Karolien Bettens ◽  
Nathalie Brouwers ◽  
Helen Van Miegroet ◽  
Ana Gil ◽  
Sebastiaan Engelborghs ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genome Wide Association ◽  
Onset Age ◽  
Susceptibility Loci ◽  
Follow Up Study ◽  
Genome Wide

scholarly journals Multivariate Modeling of Direct and Proxy GWAS Indicates Substantial Common Variant Heritability of Alzheimer's Disease

2021 ◽  
Author(s):  
Javier de la Fuente ◽  
Andrew D. Grotzinger ◽  
Riccardo E. Marioni ◽  
Michel G. Nivard ◽  
Elliot M. Tucker-Drob
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Common Variant ◽  
Genome Wide Association Studies ◽  
Imaging Data ◽  
Genome Wide ◽  
History Of ◽  
Unbiased Estimates ◽  
Summary Data

Genome-wide association studies (GWAS) of proxy-phenotypes using family history of disease (GWAX) substantially boost power for genetic discovery when combined with direct case-control GWAS, most prominently in the context of Alzheimer's Disease (AD). However, despite twin study heritability estimates of approximately 60%, recent SNP-based estimates of common variant heritability of AD from meta-analyzed GWAS-GWAX data have been particularly low (2.5%), calling into question the prospects of continued progress in AD genetics. We demonstrate that commonly used approaches for combining GWAX and GWAS data produce dramatic underestimates of heritability, and we introduce a multivariate method for estimating individual SNP effects and recovering unbiased estimates of SNP heritability when combining GWAS and GWAX summary data. We estimate the SNP heritability of Clinical AD diagnoses excluding the APOE region at ~6-10%, with the corresponding estimate for biological AD (based on prevalence rate estimates from recently published molecular imaging data) as high as ~20%. Common variant risk for AD appears to represent a very strong effect of APOE superimposed upon a relatively diffuse polygenic signal that is distributed across the genome.

scholarly journals System-Level Analysis of Alzheimer’s Disease Prioritizes Candidate Genes for Neurodegeneration

2021 ◽  
Vol 12 ◽  
Author(s):  
Jeffrey L. Brabec ◽  
Montana Kay Lara ◽  
Anna L. Tyler ◽  
J. Matthew Mahoney
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genome Wide Association Study ◽  
Neurodegenerative Disorder ◽  
Disease Status ◽  
Cumulative Distribution ◽  
System Level ◽  
Risk Genes ◽  
Genome Wide ◽  
Prioritization Method

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder. Since the advent of the genome-wide association study (GWAS) we have come to understand much about the genes involved in AD heritability and pathophysiology. Large case-control meta-GWAS studies have increased our ability to prioritize weaker effect alleles, while the recent development of network-based functional prediction has provided a mechanism by which we can use machine learning to reprioritize GWAS hits in the functional context of relevant brain tissues like the hippocampus and amygdala. In parallel with these developments, groups like the Alzheimer’s Disease Neuroimaging Initiative (ADNI) have compiled rich compendia of AD patient data including genotype and biomarker information, including derived volume measures for relevant structures like the hippocampus and the amygdala. In this study we wanted to identify genes involved in AD-related atrophy of these two structures, which are often critically impaired over the course of the disease. To do this we developed a combined score prioritization method which uses the cumulative distribution function of a gene’s functional and positional score, to prioritize top genes that not only segregate with disease status, but also with hippocampal and amygdalar atrophy. Our method identified a mix of genes that had previously been identified in AD GWAS including APOE, TOMM40, and NECTIN2(PVRL2) and several others that have not been identified in AD genetic studies, but play integral roles in AD-effected functional pathways including IQSEC1, PFN1, and PAK2. Our findings support the viability of our novel combined score as a method for prioritizing region- and even cell-specific AD risk genes.

P4-128: Follow up of Alzheimer's disease with psychosis genome-wide association studies

2012 ◽  
Vol 8 (4S_Part_18) ◽  
pp. P676-P676
Author(s):  
Rebecca Sims ◽  
Paul Hollingworth ◽  
Robert Sweet ◽  
Sebastiaan Engelborghs ◽  
Gianfranco Spalletta ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Genome‐wide association analyses identify genes modifying age‐at‐onset of Alzheimer’s disease

2020 ◽  
Vol 16 (S3) ◽  
Author(s):  
Eden R. Martin ◽  
Shuming Sun ◽  
Susan H. Slifer ◽  
Adam C. Naj ◽  
Xiaoyi R. Gao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Age At Onset ◽  
Genome Wide Association ◽  
Association Analyses ◽  
Genome Wide

P4-083: Genome-wide association analyses of onset age in late-onset Alzheimer's disease (LOAD) demonstrate no strong effect outside of the apolipoprotein region

2012 ◽  
Vol 8 (4S_Part_18) ◽  
pp. P662-P662
Author(s):  
Adam Naj ◽  
Yo Park ◽  
Ruchita Rajbhandary ◽  
Kara Hamilton-Nelson ◽  
Gary Beecham ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Genome Wide Association ◽  
Onset Age ◽  
Association Analyses ◽  
Genome Wide

scholarly journals Methylation-wide association analysis reveals AIM2, DGUOK, GNAI3, and ST14 genes as potential contributors to the Alzheimer’s disease pathogenesis

2018 ◽  
Author(s):  
Alireza Nazarian ◽  
Anatoliy I. Yashin ◽  
Alexander M. Kulminski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Quantitative Trait Loci ◽  
Quantitative Trait ◽  
Cognitive Abilities ◽  
Large Scale ◽  
Neurodegenerative Disorder ◽  
The United States ◽  
Association Analyses ◽  
Trait Loci

ABSTRACTIntroduction: Alzheimer’s disease (AD) is a progressive complex neurodegenerative disorder with devastating impact on cognitive abilities. It is among the top 10 leading causes of death in the United States with no curative medications. Exploring genetic and non-genetic contributors to AD development is, therefore, of great importance.Methods: We investigated the AD-associated epigenetic changes by combing results from publicly available genome-wide association analyses and a large-scale methylation quantitative trait loci study.Results: Probes mapped to 133 genes were associated with AD with < 2.50E-06. Of these, four genes (i.e., GNAI3, AIM2, DGUOK and ST14) provided stronger evidence of possible role in AD pathogenesis as they were also significantly associated with AD in previous expression quantitative trait loci analyses and/or mouse model studies.Discussion: Although the identified associations do not prove any definitive causal relationships with AD, they provide a list of prioritized genes for follow-up functional studies.

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