BackgroundOur understanding of the molecular mechanisms underlying Alzheimer’s disease (AD) remains incomplete. Previous studies have revealed that genetic factors provide a significant contribution to the pathogenesis and development of AD. In the past years, numerous genes implicated in this disease have been identified via genetic association studies on candidate genes or at the genome-wide level. However, in many cases, the roles of these genes and their interactions in AD are still unclear. A comprehensive and systematic analysis focusing on the biological function and interactions of these genes in the context of AD will therefore provide valuable insights to understand the molecular features of the disease.MethodIn this study, we collected genes potentially associated with AD by screening publications on genetic association studies deposited in PubMed. The major biological themes linked with these genes were then revealed by function and biochemical pathway enrichment analysis, and the relation between the pathways was explored by pathway crosstalk analysis. Furthermore, the network features of these AD-related genes were analyzed in the context of human interactome and an AD-specific network was inferred using the Steiner minimal tree algorithm.ResultsWe compiled 430 human genes reported to be associated with AD from 823 publications. Biological theme analysis indicated that the biological processes and biochemical pathways related to neurodevelopment, metabolism, cell growth and/or survival, and immunology were enriched in these genes. Pathway crosstalk analysis then revealed that the significantly enriched pathways could be grouped into three interlinked modules—neuronal and metabolic module, cell growth/survival and neuroendocrine pathway module, and immune response-related module—indicating an AD-specific immune-endocrine-neuronal regulatory network. Furthermore, an AD-specific protein network was inferred and novel genes potentially associated with AD were identified.ConclusionBy means of network and pathway-based methodology, we explored the pathogenetic mechanism underlying AD at a systems biology level. Results from our work could provide valuable clues for understanding the molecular mechanism underlying AD. In addition, the framework proposed in this study could be used to investigate the pathological molecular network and genes relevant to other complex diseases or phenotypes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-017-0252-z) contains supplementary material, which is available to authorized users.

Motivation Alzheimer’s disease (AD) is a serious degenerative brain disease and the most common cause of dementia. The current available drugs for AD provide symptomatic benefit, but there is no effective drug to cure the disease. The emergence of large-scale genomic, pharmacological data provides new opportunities for drug discovery and drug repositioning as a promising strategy in searching novel drug for AD. Results In this study, we took advantage of our increasing understanding based on systems biology approaches on the pathway and network levels and perturbation data sets from the Library of Integrated Network-Based Cellular Signatures (LINCS) to introduce a systematic computational process to discover new drugs implicated in AD. Firstly, we collected 561 genes that have reported to be risk genes of AD, and applied functional enrichment analysis on these genes. Then, by quantifying proximity between 5595 molecule drugs and AD based on human interactome, we filtered out 1092 drugs that were proximal to the disease. We further performed an Inverted Gene Set Enrichment analysis on these drug candidates, which allowed us to estimate effect of perturbations on gene expression and identify 24 potential drug candidates for AD treatment. Results from this study also provided insights for understanding the molecular mechanisms underlying AD. As a useful systematic method, our approach can also be used to identify efficacious therapies for other complex diseases. Supplementary information Supplementary data are available at Bioinformatics online.

Introduction:Major depressive disorder (MDD) is a mental disorder caused by the combination of genetic, environmental, and psychological factors. Over the years, a number of genes potentially associated with MDD have been identified. However, in many cases, the role of these genes and their relationship in the etiology and development of MDD remains unclear. Under such situation, a systems biology approach focusing on the function correlation and interaction of the candidate genes in the context of MDD will provide useful information on exploring the molecular mechanisms underlying the disease. Methods:We collected genes potentially related to MDD by screening the human genetic studies deposited in PubMed (https ://www.ncbi.nlm.nih.gov/pubmed). The main biological themes within the genes were explored by function and pathway enrichment analysis.Then, the interaction of genes was analyzed in the context of protein-protein interaction network and a MDD-specific network was built by Steiner minimal tree algorithm. Results:We collected 255 candidate genes reported to be associated with MDD from available publications. Functional analysis revealed that biological processes and biochemical pathways related to neuronal development, endocrine, cell growth and/or survivals, and immunology were enriched in these genes. The pathways could be largely grouped into three modules involved in biological procedures related to nervous system, the immune system, and the endocrine system, respectively. From the MDD-specific network, 35 novel genes potentially associated with the disease were identified. Conclusion:By means of network-and pathway-based methods, we explored the molecular mechanism underlying the pathogenesis of MDD at a systems biology level. Results from our work could provide valuable clues for understanding the molecular features of MDD. K E Y W O R D Smajor depressive disorder, network analysis, pathway cross talk 2 of 16 | FAN et Al.

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Major depressive disorder (MDD) is a serious mental disease with negative effects on both mental and physical health of the patient. Currently, antidepressants are among the major ways to ease or treat MDD. However, the existing antidepressants have limited efficacy in treating MDD, with a large fraction of patients either responding inadequately or differently to antidepressants during the treatment. Pharmacogenetics studies have found that the genetic features of some genes are associated with the antidepressant efficacy. In order to obtain a better understanding on the relationship between the genetic factors and antidepressant treatment response, we compiled a list of 233 single-nucleotide polymorphisms (SNPs) significantly associated with the antidepressant efficacy in treating MDD. Of the 13 non-synonymous SNPs in the list, three (rs1065852, rs3810651, and rs117986340) may influence the structures and function of the corresponding proteins. Besides, the influence of rs1065852 on the structure of CYP2D6 was further investigated via molecular dynamics simulations. Our results showed that compared to the native CYP2D6 the flexibility of the F-G loop was reduced in the mutant. As a portion of the substrate access channel, the lower flexibility of F-G loop may reduce the ability of the substrates to enter the channel, which may be the reason for the lower enzyme activity of mutant. This study may help us to understand the impact of genetic variation on antidepressant efficacy and provide clues for developing new antidepressants.

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The nicotinic acetylcholine receptors (nAChR) belong to a large family of ligand-gated ion channels and are involved in the mediation of fast synaptic transmission. Each receptor is made up of five subunits that arrange symmetrically around a central pore. Despite the similarity in their sequences and structures, the properties of these subunits vary significantly. Thus, identifying the function-related sites specific to each subunit is essential for understanding the characteristics of the subunits and the receptors assembled by them. In this study, we examined the sequence features of the nine neuronal nAChRs subunits from twelve representative vertebrate species. Analysis revealed that all the subunits were subject to strong purifying selection in evolution, and each was under a unique pattern of selection pressures. At the same time, the functional constraints were not uniform within each subunit, with different domains in the molecule being subject to different selection pressures. Via evolutionary analyses, we also detected potential positive selection events in the subunits or subunit clusters, and identified the sites might be associated with the function specificity of each subunit. Furthermore, positive selection at some domains might contributed to the diversity of subunit function; for example, the β9 strand might be related to the agonist specificity of α subunit in heteromeric receptor and β4-β5 linker could be involved in Ca2+ permeability. Subunits α7, α4 and β2 subunits possess a strong adaptability in vertebrates. Our results highlighted the importance of tracking functional differentiation in protein sequence underlying functional properties of nAChRs. In summary, our work may provide clues on understanding the diversity and the function specificity of the nAChR subunits, as well as the receptors co-assembled by them.