scholarly journals Inferring the molecular mechanisms of noncoding Alzheimer’s disease-associated genetic variants

2018 ◽  
Author(s):  
Alexandre Amlie-Wolf ◽  
Mitchell Tang ◽  
Jessica Way ◽  
Beth Dombroski ◽  
Ming Jiang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Genome Wide Association Study ◽  
Late Onset ◽  
Regulatory Mechanisms ◽  
Luciferase Expression ◽  
Tissue Specific ◽  
Causal Variants

Structured AbstractINTRODUCTIONWe set out to characterize the causal variants, regulatory mechanisms, tissue contexts, and target genes underlying noncoding late-onset Alzheimer’s Disease (LOAD)-associated genetic signals.METHODSWe applied our INFERNO method to the IGAP genome-wide association study (GWAS) data, annotating all potentially causal variants with tissue-specific regulatory activity. Bayesian co-localization analysis of GWAS summary statistics and eQTL data was performed to identify tissue-specific target genes.RESULTSINFERNO identified enhancer dysregulation in all 19 tag regions analyzed, significant enrichments of enhancer overlaps in the immune-related blood category, and co-localized eQTL signals overlapping enhancers from the matching tissue class in ten regions (ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, EPHA1, FERMT2, ZCWPW1). We validated the allele-specific effects of several variants on enhancer function using luciferase expression assays.DISCUSSIONIntegrating functional genomics with GWAS signals yielded insights into the regulatory mechanisms, tissue contexts, and genes affected by noncoding genetic variation associated with LOAD risk.

scholarly journals PRECISION MEDICINE - THE GOLDEN GATE FOR DETECTION, TREATMENT AND PREVENTION OF ALZHEIMER’S DISEASE

2016 ◽  
pp. 1-17
Author(s):  
H. Hampel ◽  
S.E. O’Bryant ◽  
J.I. Castrillo ◽  
C. Ritchie ◽  
K. Rojkova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Precision Medicine ◽  
Molecular Mechanisms ◽  
Clinical Symptoms ◽  
Late Onset ◽  
Therapeutic Success ◽  
Preclinical Stage ◽  
Treatment And Prevention

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer’s disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical “one-size-fits-all” approach in drug discovery towards biomarker guided “molecularly” tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic.

scholarly journals Network propagation of rare variants in Alzheimer’s disease reveals tissue-specific hub genes and communities

2021 ◽  
Vol 17 (1) ◽  
pp. e1008517
Author(s):  
Marzia Antonella Scelsi ◽  
Valerio Napolioni ◽  
Michael D. Greicius ◽  
Andre Altmann ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rare Variants ◽  
Late Onset ◽  
Integrative Approach ◽  
Specific Gene ◽  
Tissue Specific ◽  
Association Testing ◽  
Wide Range ◽  
Network Propagation

State-of-the-art rare variant association testing methods aggregate the contribution of rare variants in biologically relevant genomic regions to boost statistical power. However, testing single genes separately does not consider the complex interaction landscape of genes, nor the downstream effects of non-synonymous variants on protein structure and function. Here we present the NETwork Propagation-based Assessment of Genetic Events (NETPAGE), an integrative approach aimed at investigating the biological pathways through which rare variation results in complex disease phenotypes. We applied NETPAGE to sporadic, late-onset Alzheimer’s disease (AD), using whole-genome sequencing from the AD Neuroimaging Initiative (ADNI) cohort, as well as whole-exome sequencing from the AD Sequencing Project (ADSP). NETPAGE is based on network propagation, a framework that models information flow on a graph and simulates the percolation of genetic variation through tissue-specific gene interaction networks. The result of network propagation is a set of smoothed gene scores that can be tested for association with disease status through sparse regression. The application of NETPAGE to AD enabled the identification of a set of connected genes whose smoothed variation profile was robustly associated to case-control status, based on gene interactions in the hippocampus. Additionally, smoothed scores significantly correlated with risk of conversion to AD in Mild Cognitive Impairment (MCI) subjects. Lastly, we investigated tissue-specific transcriptional dysregulation of the core genes in two independent RNA-seq datasets, as well as significant enrichments in terms of gene sets with known connections to AD. We present a framework that enables enhanced genetic association testing for a wide range of traits, diseases, and sample sizes.

scholarly journals Genetic meta-analysis identifies 9 novel loci and functional pathways for Alzheimer’s disease risk

2018 ◽  
Author(s):  
Iris E Jansen ◽  
Jeanne E Savage ◽  
Kyoko Watanabe ◽  
Julien Bryois ◽  
Dylan M Williams ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Late Onset ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
Cell Types ◽  
Mendelian Randomisation ◽  
Genome Wide

AbstractLate onset Alzheimer’s disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.

scholarly journals A genome-wide association study for late-onset Alzheimer's disease using DNA pooling

2008 ◽  
Vol 1 (1) ◽  
Author(s):  
Richard Abraham ◽  
Valentina Moskvina ◽  
Rebecca Sims ◽  
Paul Hollingworth ◽  
Angharad Morgan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Late Onset ◽  
Genome Wide Association ◽  
Dna Pooling ◽  
Genome Wide ◽  
A Genome

A genome-wide association study of late-onset Alzheimer’s disease in a Japanese population

2015 ◽  
Vol 25 (4) ◽  
pp. 139-146 ◽  
Author(s):  
Atsushi Hirano ◽  
Tomoyuki Ohara ◽  
Atsushi Takahashi ◽  
Masayuki Aoki ◽  
Yuta Fuyuno ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Study ◽  
Japanese Population ◽  
Genome Wide Association Study ◽  
Late Onset ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

P2-083: Computational Identification of Regulatory Mechanisms Affected By Noncoding Variants Associated with Late-Onset Alzheimer's Disease

2016 ◽  
Vol 12 ◽  
pp. P640-P641
Author(s):  
Alexandre Amlie-Wolf ◽  
Mitchell Tang ◽  
Jessica King ◽  
Beth A. Dombroski ◽  
Li-San Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Regulatory Mechanisms ◽  
Computational Identification

P1-100: Genome-wide association study for late-onset Alzheimer's disease in the Mid-Western U.S. Amish

2010 ◽  
Vol 6 ◽  
pp. S203-S203
Author(s):  
A.C. Cummings ◽  
L. Jiang ◽  
D. Velez Edwards ◽  
R. Laux ◽  
L.L. McFarland ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Late Onset ◽  
Genome Wide Association ◽  
Genome Wide
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