scholarly journals Genome Wide Meta-Analysis identifies new loci associated with cardiac phenotypes and uncovers a common genetic signature shared by heart function and Alzheimer’s disease

2018 ◽  
Author(s):  
MªEugenia Sáez ◽  
Antonio González-Pérez ◽  
Begoña Hernández-Olasagarre ◽  
Aida Beà ◽  
Sonia Moreno-Grau ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cardiac Function ◽  
Heart Development ◽  
Heart Function ◽  
Experimental Models ◽  
Association Analyses ◽  
Genome Wide ◽  
Apoptotic Genes ◽  
The Impact

ABSTRACTAimsEchocardiography has become an indispensable tool for the study of heart performance, improving the monitoring of individuals with cardiac diseases. Diverse genetic factors associated with echocardiographic measures of heart structure and functions have been previously reported. The impact of several apoptotic genes in heart development identified in experimental models prompted us to assess their potential association with indicators of human cardiac function. This study started with the aim to investigate the possible association of variants of apoptotic genes with echocardiographic traits and to identify new genetic markers associated with cardiac function.Methods and resultsGenome wide data from different studies were obtained from public repositories. After quality control and imputation, association analyses confirm the role of caspases and other apoptosis related genes with cardiac phenotypes. Moreover, enrichment analysis showed an over-representation of genes, including some apoptotic regulators, associated with Alzheimer’s disease (AD). We further explored this unexpected observation which was confirmed by genetic correlation analyses.ConclusionsOur findings show the association of apoptotic gene variants with echocardiographic indicators of heart function and reveal a novel potential genetic link between echocardiographic measures in healthy populations and cognitive decline later on in life. These findings may have important implications for preventative strategies combating Alzheimer’s disease.

scholarly journals Genome Wide Meta-Analysis identifies common genetic signatures shared by heart function and Alzheimer’s disease

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
M. E. Sáez ◽  
A. González-Pérez ◽  
B. Hernández-Olasagarre ◽  
A. Beà ◽  
S. Moreno-Grau ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cardiac Function ◽  
Heart Development ◽  
Heart Function ◽  
Meta Analysis ◽  
Genome Wide ◽  
Study Results ◽  
Apoptotic Genes ◽  
The Impact

Abstract Echocardiography has become an indispensable tool for the study of heart performance, improving the monitoring of individuals with cardiac diseases. Diverse genetic factors associated with echocardiographic measures have been previously reported. The impact of several apoptotic genes in heart development identified in experimental models prompted us to assess their potential association with human cardiac function. This study aimed at investigating the possible association of variants of apoptotic genes with echocardiographic traits and to identify new genetic markers associated with cardiac function. Genome wide data from different studies were obtained from public repositories. After quality control and imputation, a meta-analysis of individual association study results was performed. Our results confirmed the role of caspases and other apoptosis related genes with cardiac phenotypes. Moreover, enrichment analysis showed an over-representation of genes, including some apoptotic regulators, associated with Alzheimer’s disease. We further explored this unexpected observation which was confirmed by genetic correlation analyses. Our findings show the association of apoptotic gene variants with echocardiographic indicators of heart function and reveal a novel potential genetic link between echocardiographic measures in healthy populations and cognitive decline later on in life. These findings may have important implications for preventative strategies combating Alzheimer’s disease.

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 Genetic Insights into the Impact of Complement in Alzheimer’s Disease

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1990
Author(s):  
Megan Torvell ◽  
Sarah M. Carpanini ◽  
Nikoleta Daskoulidou ◽  
Robert A. J. Byrne ◽  
Rebecca Sims ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Complement Activation ◽  
Association Studies ◽  
Screening Tests ◽  
Diagnostic Tools ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Activation Products ◽  
The Impact

The presence of complement activation products at sites of pathology in post-mortem Alzheimer’s disease (AD) brains is well known. Recent evidence from genome-wide association studies (GWAS), combined with the demonstration that complement activation is pivotal in synapse loss in AD, strongly implicates complement in disease aetiology. Genetic variations in complement genes are widespread. While most variants individually have only minor effects on complement homeostasis, the combined effects of variants in multiple complement genes, referred to as the “complotype”, can have major effects. In some diseases, the complotype highlights specific parts of the complement pathway involved in disease, thereby pointing towards a mechanism; however, this is not the case with AD. Here we review the complement GWAS hits; CR1 encoding complement receptor 1 (CR1), CLU encoding clusterin, and a suggestive association of C1S encoding the enzyme C1s, and discuss difficulties in attributing the AD association in these genes to complement function. A better understanding of complement genetics in AD might facilitate predictive genetic screening tests and enable the development of simple diagnostic tools and guide the future use of anti-complement drugs, of which several are currently in development for central nervous system disorders.

scholarly journals The impact of anorexigenic peptides in experimental models of Alzheimer’s disease pathology

2019 ◽  
Vol 240 (2) ◽  
pp. R47-R72 ◽  
Author(s):  
Lenka Maletínská ◽  
Andrea Popelová ◽  
Blanka Železná ◽  
Michal Bencze ◽  
Jaroslav Kuneš
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Energy Homeostasis ◽  
Neurodegenerative Disorder ◽  
Experimental Studies ◽  
The Elderly ◽  
Experimental Models ◽  
New Drugs ◽  
Neuroprotective Effects ◽  
The Impact

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder in the elderly population. Numerous epidemiological and experimental studies have demonstrated that patients who suffer from obesity or type 2 diabetes mellitus have a higher risk of cognitive dysfunction and AD. Several recent studies demonstrated that food intake-lowering (anorexigenic) peptides have the potential to improve metabolic disorders and that they may also potentially be useful in the treatment of neurodegenerative diseases. In this review, the neuroprotective effects of anorexigenic peptides of both peripheral and central origins are discussed. Moreover, the role of leptin as a key modulator of energy homeostasis is discussed in relation to its interaction with anorexigenic peptides and their analogs in AD-like pathology. Although there is no perfect experimental model of human AD pathology, animal studies have already proven that anorexigenic peptides exhibit neuroprotective properties. This phenomenon is extremely important for the potential development of new drugs in view of the aging of the human population and of the significantly increasing incidence of AD.

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

scholarly journals Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer’s disease and three causality networks of AD: the GR@ACE project

2019 ◽  
Author(s):  
Sonia Moreno-Grau ◽  
Itziar de Rojas ◽  
Isabel Hernández ◽  
Inés Quintela ◽  
Laura Montrreal ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Meta Analysis ◽  
Biological Pathways ◽  
Amyloid Angiopathy ◽  
Clinical Heterogeneity ◽  
Genome Wide ◽  
A Genome ◽  
Co Morbidity ◽  
The Impact

AbstractBackgroundGenetics plays a major role in Alzheimer’s Disease (AD). To date, 40 genes associated with AD have been identified, although most remain undiscovered. Clinical, neuropathological and genetic variability might impact genetic discoveries and complicate dissection of the biological pathways underlying AD.MethodsGR@ACE is a genome-wide study of dementia and its clinical endophenotypes that encompasses 4,120 cases and 3,289 controls from Spain. GR@ACE phenotypes were defined according to AD’s clinical certainty and the presence of vascular co-morbidity. To explore whether clinical endophenotypes reflect variation in underlying biological pathways, we first assessed the impact of known AD loci across endophenotypes to generate three loci categories. Next, we incorporated gene co-expression data and conducted pathway analysis on each category. To assess the impact of heterogeneity in the GWAS findings, the GR@ACE series were meta-analyzed with: 1) genotype-level data from dbGaP (N=21,235); and 2) summary statistics from IGAP Stages I and II (n=61,571 and n=81,455 respectively).FindingsWe classified known AD loci in three categories, which might reflect the disease clinical heterogeneity, from vascular and mixed forms to pure AD pathology. Immune system pathways were detected in all categories. Intriguingly, vascular processes were only detected as a causal mechanism in probable AD. A meta-analysis of GR@ACE with additional GWAS datasets revealed theANKRD31-rs4704171signal in theHMGCRgenomic region. We confirmed NDUFAF6-rs10098778 andSCIMP-rs7225151, which were previously detected by IGAP, to be suggestive signals. We also confirmed CD33-rs3865444 to be genome-wide significant.InterpretationThe regulation of vasculature is a prominent causal component of probable AD. In that context, cerebral amyloid angiopathy, the unique identified link between the vascular and amyloid hypotheses, deserves further investigation. The GR@ACE meta-analysis revealed novel AD genetic signals. GWAS results are strongly driven by the presence of clinical heterogeneity in the AD series.FundingGrifols SA, Fundación bancaria “La Caixa”, Fundació ACE and ISCIII (Instituto de Salud Carlos III).

Perturbed endoplasmic reticulum function, synaptic apoptosis and the pathogenesis of Alzheimer's disease

2001 ◽  
Vol 67 ◽  
pp. 151-162 ◽  
Author(s):  
Mark P. Mattson ◽  
Devin S. Gary ◽  
Sic L. Chan ◽  
Wenzhen Duan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Neuronal Degeneration ◽  
Focal Point ◽  
Experimental Models ◽  
Proteolytic Processing ◽  
App Processing ◽  
The Impact ◽  
Er Calcium

Endoplasmic reticulum (ER) appears to be a focal point for alterations that result in neuronal dysfunction and death in Alzheimer's disease (AD). Aberrant proteolytic processing and/or trafficking of the ϐ-amyloid precursor protein (APP) in ER may promote neuronal degeneration by increasing the levels of the neurotoxic forms of ϐ-amyloid (Aϐ) and by decreasing the levels of the neuroprotective secreted form of APP (sAPPα). Some cases of AD are caused by mutations in the genes encoding presenilin 1 (PS1). When expressed in cultured neuronal cells and transgenic mice, PS1 mutations cause abnormalities in ER calcium homoeostasis, enhancing the calcium responses to stimuli that activate IP3- and ryanodine-sensitive ER calcium pools. Two major consequences of this disrupted ER calcium regulation are altered proteolytic processing of APP and increased vulnerability of neurons to apoptosis and excitotoxicity. The impact of PS1 mutations and aberrant APP processing is particularly great in synaptic terminals. Perturbed synaptic calcium homoeostasis promotes activation of apoptotic cascades involving production of Par-4 (prostate apoptosis response-4), mitochondrial dysfunction and caspase activation. Aϐ 42 (the 42-amino-acid form of Aϐ) induces membrane lipid peroxidation in synapses and dendrites resulting in impairment of membrane ion-motive ATPases and glucose and glutamate transporters. This disrupts synaptic ion and energy homoeostasis thereby promoting synaptic degeneration. In contrast, sAPPα activates signalling pathways that protect synapses against excitotoxicity and apoptosis. In the more common sporadic forms of AD, the initiating causes of the neurodegenerative cascade are less well defined, but probably involve increased levels of oxidative stress and impaired energy metabolism. Such alterations have been shown to disrupt neuronal calcium homoeostasis in experimental models, and may therefore feed into the same neurodegenerative cascade initiated by mutations in presenilins and APP. Perturbed synaptic ER calcium homoeostasis and consequent alterations in APP processing appear to be pivotal events in both sporadic and familial forms of AD.

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
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