Showing posts with label pathways. Show all posts
Showing posts with label pathways. Show all posts
Genome-wide pathway analysis of memory impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks.
Memory deficits are prominent features of mild cognitive impairment (MCI) and Alzheimer's disease (AD). The genetic architecture underlying these memory deficits likely involves the combined effects of multiple genetic variants operative within numerous biological pathways. In order to identify functional pathways associated with memory impairment, we performed a pathway enrichment analysis on genome-wide association data from 742 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. A composite measure of memory was generated as the phenotype for this analysis by applying modern psychometric theory to item-level data from the ADNI neuropsychological test battery. Using the GSA-SNP software tool, we identified 27 canonical, expertly-curated pathways with enrichment (FDR-corrected p-value < 0.05) against this composite memory score. Processes classically understood to be involved in memory consolidation, such as neurotransmitter receptor-mediated calcium signaling and long-term potentiation, were highly represented among the enriched pathways. In addition, pathways related to cell adhesion, neuronal differentiation and guided outgrowth, and glucose- and inflammation-related signaling were also enriched. Among genes that were highly-represented in these enriched pathways, we found indications of coordinated relationships, including one large gene set that is subject to regulation by the SP1 transcription factor, and another set that displays co-localized expression in normal brain tissue along with known AD risk genes. These results 1) demonstrate that psychometrically-derived composite memory scores are an effective phenotype for genetic investigations of memory impairment and 2) highlight the promise of pathway analysis in elucidating key mechanistic targets for future studies and for therapeutic interventions.
Translational Psychiatry - Multiple variants aggregate in the neuregulin signaling pathway in a subset of schizophrenia patients
Despite the strongly held view that schizophrenia (SZ) shows substantial genetic heterogeneity, pathway heterogeneity, as seen in cancer where different pathways are affected in similar tumors, has not been explored. We explore this possibility in a case-only study of the neuregulin signaling pathway (NSP), which has been prominently implicated in SZ and for which there is detailed knowledge on the ligand- and receptor-processing steps through β- and γ-secretase cleavage. We hypothesize that more than one damaging variants in the NSP genes might be necessary to cause disease, leading to an apparent clustering of such variants in only the few patients with affected NSP. We analyze linkage and next-generation sequencing results for the genes encoding components of the pathway, including NRG1, NRG3, ERBB4, β-secretase and the γ-secretase complex. We find multiple independent examples of supporting evidence for this hypothesis: (i) increased linkage scores over NSP genes, (ii) multiple positive interlocus correlations of linkage scores across families suggesting each family is linked to either many or none of the genes, (iii) aggregation of predicted damaging variants in a subset of individuals and (iv) significant phenotypic differences of the subset of patients carrying such variants. Collectively, our data strongly support the hypothesis that the NSP is affected by multiple damaging variants in a subset of phenotypically distinct patients. On the basis of this, we propose a general model of pathway heterogeneity in SZ, which, in part, may explain its phenotypic variability and genetic complexity.
EnrichNet: network-based gene set enrichment analysis.
Assessing functional associations between an experimentally derived gene or protein set of interest and a database of known gene/protein sets is a common task in the analysis of large-scale functional genomics data. For this purpose, a frequently used approach is to apply an over-representation-based enrichment analysis. However, this approach has four drawbacks: (i) it can only score functional associations of overlapping gene/proteins sets; (ii) it disregards genes with missing annotations; (iii) it does not take into account the network structure of physical interactions between the gene/protein sets of interest and (iv) tissue-specific gene/protein set associations cannot be recognized.
RESULTS:
To address these limitations, we introduce an integrative analysis approach and web-application called EnrichNet. It combines a novel graph-based statistic with an interactive sub-network visualization to accomplish two complementary goals: improving the prioritization of putative functional gene/protein set associations by exploiting information from molecular interaction networks and tissue-specific gene expression data and enabling a direct biological interpretation of the results. By using the approach to analyse sets of genes with known involvement in human diseases, new pathway associations are identified, reflecting a dense sub-network of interactions between their corresponding proteins.
AVAILABILITY:
EnrichNet is freely available at http://www.enrichnet.org
Cell - Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease
The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer’s disease (LOAD), we constructed gene-regulatory networks in 1,647 postmortem brain tissues from LOAD patients and nondemented subjects, and we demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune- and microglia-specific module that is dominated by genes involved in pathogen phagocytosis, contains TYROBP as a key regulator, and is upregulated in LOAD. Mouse microglia cells overexpressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a framework to test models of disease mechanisms underlying LOAD.
Futurity.org – From genes to brain: Schizophrenia untangled
The genomic pathway, Integrative Nuclear FGFR 1 Signaling (INFS), is a central intersection point for multiple pathways of as many as 160 different genes believed to be involved in the disorder.
Schizophrenia genetic networks identified: Connection to autism found
Although schizophrenia is highly genetic in origin, the genes involved in the disorder have been difficult to identify. In the past few years, researchers have implicated several genes, but it is unclear how they act to produce the disorder. A new study by researchers at Columbia University Medical Center identifies affected gene networks and provides insight into the molecular causes of the disease.
Read more at: http://medicalxpress.com/news/2012-11-schizophrenia-genetic-networks-autism.html#jCp
Read more at: http://medicalxpress.com/news/2012-11-schizophrenia-genetic-networks-autism.html#jCp
Identifying aberrant pathways through integrated analysis of knowledge in pharmacogenomics
Many complex diseases are the result of abnormal pathway functions instead of single abnormalities. Disease diagnosis and intervention strategies must target these pathways while minimizing the interference with normal physiological processes. Large-scale identification of disease pathways and chemicals that may be used to perturb them requires the integration of information about drugs, genes, diseases and pathways. This information is currently distributed over several pharmacogenomics databases. An integrated analysis of the information in these databases can reveal disease pathways and facilitate novel biomedical analyses.
Results: We demonstrate how to integrate pharmacogenomics databases through integration of the biomedical ontologies that are used as meta-data in these databases. The additional background knowledge in these ontologies can then be used to enable novel analyses. We identify disease pathways using a novel multi-ontology enrichment analysis over the Human Disease Ontology, and we identify significant associations between chemicals and pathways using an enrichment analysis over a chemical ontology. The drug–pathway and disease–pathway associations are a valuable resource for research in disease and drug mechanisms and can be used to improve computational drug repurposing.
Availability: http://pharmgkb-owl.googlecode.com
KEGG pathway analysis of the genes implicated in chronic fatigue syndrome
There are relatively few genetic studies on chronic fatigue syndrome /fibromyalgia compared to other disorders, and a systems biology approach is necessarily limited. The main thrust so far seems to be related to neurotransmitter systems,(dopamine/ glutamate and serotonin) but also to the immune network and viral and pathogen related pathways.
Galaxy DNA-analysis software is now available 'in the cloud'
Galaxy is an open, web-based platform for data intensive biomedical research. Whether on the free public server or your own instance, you can perform, reproduce, and share complete analyses.
Anorexia genes and KEGG Pathways
Anorexia genes lag far behind those of other disorders in terms of numbers: This KEGG pathway analysis povides some details of those so far identified. Dopamine, glutamate, GABA , neurotrophin and adipocytokine pathways figure most prominently.
Aegean Conferences: 10th International Conference on Pathways, Networks, and Systems Medicine
Image via WikipediaWith the availability of whole genome sequences, research attention shifts from gene sequences and genome content to protein functions and systems biology. Genes comprise a major component of the ‘parts list’ that is required for building and maintaining of living organisms. Genome DNA sequences reveal the genetic inventory for a rapidly increasing number of species. Defining and interpreting the instruction manual for protein functions, individually and collectively, is the emerging challenge.
Defining protein functions is a complex problem because each gene typically encodes several distinct proteins. As a result, the protein inventory includes as many as 100,000 distinct proteins. Protein functions can vary with developmental stage, anatomical location, and environmental context. Like the problem of sequencing the human genome, the multidimensional nature of protein functions in time, space and context constitutes one of the ‘big’ problems in biomedical research. Resolving this problem is key to revolutionizing health care where a deep understanding of complex biological systems will lead to more powerful and specific ways to treat, and perhaps, even prevent birth defects and adult diseases. Rodos Palace Conference Center, Ixia, Rhodes, Greece
June 10-15, 2012
Alzheimer's Pathways: An update of KEGG pathways (BIN1, CD33, CD2AP. MS4A2, etc)
These pathways include novel genes and a number of new pathways recently added by KEGG: Compounds relevant to Alzheimer's disease (cholesterol, homocysteine, vitamins, etc.) have been added, and proteins related to the herpes simplex life cycle are also colour-coded.
Alzheimer's genes and risk factors :
Alzheimer's genes and risk factors :
Exosome Explosion | The Scientist
Exosomes are vesicles secreted from mammalian cells: They help to get rid of intracellular rubbish (and pathogens' proteins) but also play a role in intercellular signalling and contain microRNA (sometimes from viruses) . They play an important role in the immune system, but also in many other tissues and cell types
Shared Molecular and Functional Frameworks among Five Complex Human Disorders: A Comparative Study on Interactomes Linked to Susceptibility Genes.
Several issues related to immune function and growth factor signalling pathways appeared in all autoimmune diseases, and in Alzheimer's disease.
Huntington's disease: KEGG pathway analysis of the Huntingtin interactome
KEGG pathway analysis of the HTT huntingtin interactome in Huntington's disease
Other KEGG posts
Other KEGG pathways
Other KEGG posts
Other KEGG pathways
KEGG pathway analysis of Autism susceptibility genes
This analysis of several hundred Autism susceptibility gene candidates highlights MAPK, calcium, and neurotrophin pathways, among others, as well as numerous adhesion related networks. As with many other diseases, immune networks are well represented , as are pathogen entry and defence pathways.
Other KEGG pathway analyses of polygenic diseases
Other KEGG pathway analyses of polygenic diseases
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