The frontline of immune response in peripheral blood.

Peripheral blood is an attractive source for the discovery of disease biomarkers. Gene expression profiling of whole blood or its components has been widely conducted for various diseases. However, due to population heterogeneity and the dynamic nature of gene expression, certain biomarkers discovered from blood transcriptome studies could not be replicated in independent studies. In the meantime, it's also important to know whether a reliable biomarker is shared by several diseases or specific to certain health conditions. We hypothesized that common mechanism of immune response in blood may be shared by different diseases. Under this hypothesis, we surveyed publicly available transcriptome data on infectious and autoimmune diseases derived from peripheral blood. We examined to which extent common gene dys-regulation existed in different diseases. We also investigated whether the commonly dys-regulated genes could serve as reliable biomarkers. First, we found that a limited number of genes are frequently dys-regulated in infectious and autoimmune diseases, from which we selected 10 genes co-dysregulated in viral infections and another set of 10 genes co-dysregulated in bacterial infections. In addition to its ability to distinguish viral infections from bacterial infections, these 20 genes could assist in disease classification and monitoring of treatment effect for several infectious and autoimmune diseases. In some cases, a single gene is sufficient to serve this purpose. It was interesting that dys-regulation of these 20 genes were also observed in other types of diseases including cancer and stroke where certain genes could also serve as biomarkers for diagnosis or prognosis. Furthermore, we demonstrated that this set of 20 genes could also be used in continuous monitoring of personal health. The rich information from these commonly dys-regulated genes may find its wide application in clinical practice and personal healthcare. More validation studies and in-depth investigations are warranted in the future.

GSA: Genome Sequence Archive.

With the rapid development of sequencing technologies towards higher throughput and lower cost, sequence data are generated at an unprecedentedly explosive rate. To provide an efficient and easy-to-use platform for managing huge sequence data, here we present Genome Sequence Archive (GSA; http://bigd.big.ac.cn/gsa or http://gsa.big.ac.cn), a data repository for archiving raw sequence data. In compliance with data standards and structures of the International Nucleotide Sequence Database Collaboration (INSDC), GSA adopts four data objects (BioProject, BioSample, Experiment, and Run) for data organization, accepts raw sequence reads produced by a variety of sequencing platforms, stores both sequence reads and metadata submitted from all over the world, and makes all these data publicly available to worldwide scientific communities. In the era of big data, GSA is not only an important complement to existing INSDC members by alleviating the increasing burdens of handling sequence data deluge, but also takes the significant responsibility for global big data archive and provides free unrestricted access to all publicly available data in support of research activities throughout the world.

Towards Personalized Intervention for Alzheimer's Disease.

Alzheimer's disease (AD) remains to be a grand challenge for the international community despite over a century of exploration. A key factor likely accounting for such a situation is the vast heterogeneity in the disease etiology, which involves very complex and divergent pathways. Therefore, intervention strategies shall be tailored for subgroups of AD patients. Both demographic and in-depth information is needed for patient stratification. The demographic information includes primarily APOE genotype, age, gender, education, environmental exposure, life style, and medical history, whereas in-depth information stems from genome sequencing, brain imaging, peripheral biomarkers, and even functional assays on neurons derived from patient-specific induced pluripotent cells (iPSCs). Comprehensive information collection, better understanding of the disease mechanisms, and diversified strategies of drug development would help with more effective intervention in the foreseeable future.

Perturbation of the transcriptome: implications of the innate immune system in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with broad impact. Although Aß and tau have been proposed as the key molecules in the disease mechanism, comprehensive understanding of AD pathogenesis requires a systemic view at the genomic level. From studies on the brain transcriptome of AD, we have gradually realized the contribution of the immune system to AD development. Recent explorations on the blood transcriptome of AD patients have revealed robust immune activation in the peripheral blood. The combination of transcriptome studies and other types of studies has further elucidated the roles of specific immune pathways in distinct cell types during AD development and highlighted the critical contributions from immune genes such as TREM2.

AlzBase: an Integrative Database for Gene Dysregulation in Alzheimer's Disease.

Alzheimer's disease (AD) affects a significant portion of elderly people worldwide. Although the amyloid-ß (Aß) cascade hypothesis has been the prevailing theory for the molecular mechanism of AD in the past few decades, treatment strategies targeting the Aß cascade have not demonstrated effectiveness as yet. Thus, elucidating the spatial and temporal evolution of the molecular pathways in AD remains to be a daunting task. To facilitate novel discoveries in this filed, here, we have integrated information from multiple sources for the better understanding of gene functions in AD pathogenesis. Several categories of information have been collected, including (1) gene dysregulation in AD and closely related processes/diseases such as aging and neurological disorders, (2) correlation of gene dysregulation with AD severity, (3) a wealth of annotations on the functional and regulatory information, and (4) network connections for gene-gene relationship. In addition, we have also provided a comprehensive summary for the top ranked genes in AlzBase. By evaluating the information curated in AlzBase, researchers can prioritize genes from their own research and generate novel hypothesis regarding the molecular mechanism of AD. To demonstrate the utility of AlzBase, we examined the genes from the genetic studies of AD. It revealed links between the upstream genetic variations and downstream endo-phenotype and suggested several genes with higher priority. This integrative database is freely available on the web at http://alz.big.ac.cn/alzBase .

Common Aging Signature in the Peripheral Blood of Vascular Dementia and Alzheimer's Disease.

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most dominant forms of dementia in elderly people. Due to the large overlap between AD and VaD in clinical observations, great controversies exist regarding the distinction and connection between these two types of senile dementia. Here for the first time, we resort to the gene expression pattern of the peripheral blood to compare AD and VaD objectively. In our previous work, we have demonstrated that the dysregulation of gene expression in AD is unique among the examined diseases including neurological diseases, cancer, and metabolic diseases. In this study, we found that the dysregulation of gene expression in AD and VaD is quite similar to each other at both functional and gene levels. Interestingly, the dysregulation started at the early stages of the diseases, namely mild cognitive impairment (MCI) and vascular cognitive impairment (VCI). We have also shown that this signature is distinctive from that of peripheral vascular diseases. Comparison with aging studies revealed that the most profound change in AD and VaD, namely ribosome, is consistent with the accelerated aging scenario. This study may have implications to the common mechanism between AD and VaD.

Alzheimer's Disease: Genomics and Beyond.

Alzheimer's disease (AD) is a major form of senile dementia. Despite the critical roles of Aß and tau in AD pathology, drugs targeting Aß or tau have so far reached limited success. The advent of genomic technologies has made it possible to gain a more complete picture regarding the molecular network underlying the disease progression which may lead to discoveries of novel treatment targets. In this review, we will discuss recent progresses in AD research focusing on genome, transcriptome, epigenome, and related subjects. Advancements have been made in the finding of novel genetic risk factors, new hypothesis for disease mechanism, candidate biomarkers for early diagnosis, and potential drug targets. As an integration effort, we have curated relevant data in a database named AlzBase.

Web resources for stem cell research.

In this short review, we have presented a brief overview on major web resources relevant to stem cell research. To facilitate more efficient use of these resources, we have provided a preliminary rating based on our own user experience of the overall quality for each resource. We plan to update the information on an annual basis.

Genomics in neurological disorders.

Neurological disorders comprise a variety of complex diseases in the central nervous system, which can be roughly classified as neurodegenerative diseases and psychiatric disorders. The basic and translational research of neurological disorders has been hindered by the difficulty in accessing the pathological center (i.e., the brain) in live patients. The rapid advancement of sequencing and array technologies has made it possible to investigate the disease mechanism and biomarkers from a systems perspective. In this review, recent progresses in the discovery of novel risk genes, treatment targets and peripheral biomarkers employing genomic technologies will be discussed. Our major focus will be on two of the most heavily investigated neurological disorders, namely Alzheimer's disease and autism spectrum disorder.

Hidden risk genes with high-order intragenic epistasis in Alzheimer's disease.

Meta-analysis of data from genome-wide association studies (GWAS) of Alzheimer's disease (AD) has confirmed the high risk of APOE and identified twenty other risk genes/loci with moderate effect size. However, many more risk genes/loci remain to be discovered to account for the missing heritability. The contributions from individual singe-nucleotide polymorphisms (SNPs) have been thoroughly examined in traditional GWAS data analysis, while SNP-SNP interactions can be explored by a variety of alternative approaches. Here we applied generalized multifactor dimensionality reduction to the re-analysis of four publicly available GWAS datasets for AD. When considering 4-order intragenic SNP interactions, we observed high consistency of discovered potential risk genes among the four independent GWAS datasets. Ten potential risk genes were observed across all four datasets, including PDE1A, RYR3, TEK, SLC25A21, LOC729852, KIRREL3, PTPN5, FSHR, PARK2, and NR3C2. These potential risk genes discovered by generalized multifactor dimensionality reduction are highly relevant to AD pathogenesis based on multiple layers of evidence. The genetic contributions of these genes warrant further confirmation in other independent GWAS datasets for AD.

Robust gene dysregulation in Alzheimer's disease brains.

The brain transcriptome of Alzheimer's disease (AD) reflects the prevailing disease mechanism at the gene expression level. However, thousands of genes have been reported to be dysregulated in AD brains in existing studies, and the consistency or discrepancy among these studies has not been thoroughly examined. Toward this end, we conducted a comprehensive survey of the brain transcriptome datasets for AD and other neurological diseases. We first demonstrated that the frequency of observed dysregulation in AD was highly correlated with the reproducibility of the dysregulation. Based on this observation, we selected 100 genes with the highest frequency of dysregulation to illustrate the core perturbation in AD brains. The dysregulation of these genes was validated in several independent datasets for AD. We further identified 12 genes with strong correlation of gene expression with disease progression. The relevance of these genes to disease progression was also validated in an independent dataset. Interestingly, we found a transcriptional "cushion" for these 100 genes in the less vulnerable visual cortex region, which may be a critical component of the protection mechanism for less vulnerable brain regions. To facilitate the research in this field, we have provided the expression information of ~8000 relevant genes on a publicly accessible web server AlzBIG (http://alz.big.ac.cn).