Lost in the space of bioinformatic tools: A constantly updated survival guide for genetic epidemiology. The GenEpi Toolbox
ABSTRACT Genome-wide association studies (GWASs) led to impressive advances in the elucidation of genetic factors underlying complex phenotypes and diseases. However, the ability of GWAS to identify new susceptibility loci in a hypothesis-free approach requires tools to quickly retrieve comprehensive information about a genomic region and analyze the potential effects of coding and non-coding SNPs in a candidate gene region. Furthermore, once a candidate region is chosen for resequencing and fine-mapping studies, the identification of several rare mutations is likely and requires strong bioinformatic support to properly evaluate and prioritize the found mutations for further analysis. Due to the variety of regulatory layers that can be affected by a mutation, a comprehensive in-silico evaluation of candidate SNPs can be a demanding and very time-consuming task. Although many bioinformatic tools that significantly simplify this task were made available in the last years, their utility is often still unknown to researches not intensively involved in bioinformatics. We present a comprehensive guide of 64 tools and databases to bioinformatically analyze gene regions of interest to predict SNP effects. In addition, we discuss tools to perform data mining of large genetic regions, predict the presence of regulatory elements, make in-silico evaluations of SNPs effects and address issues ranging from interactome analysis to graphically annotated proteins sequences. Finally, we exemplify the use of these tools by applying them to hits of a recently performed GWAS. Taken together a combination of the discussed tools are summarized and constantly updated in the web-based "GenEpi Toolbox" (http://genepi_toolbox.i-med.ac.at) and can help to get a glimpse at the potential functional relevance of both large genetic regions and single nucleotide mutations which might help to prioritize the next steps.
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ABSTRACT: 12.1 INTRODUCTION The fi rst draft of the human genome sequence was published in 2001 (Lander et al., 2001; Venter et al., 2001) and contains 90% of the 3 billion bases, with the completed sequence published in 2004 (International Human Genome Sequencing [IHGS] Consortium, 2004). The most important feature of the sequence was that the number of genes in the human genome was a lot smaller than the earlier estimate of 50,000–140,000. In the recent version of human genome built (NCBI 37.1,?taxid=9606), there are 33,897 transcripts, 21,901 of which are annotated genes (including predicted genes). There are also 3031 nonprotein coding genes with an RNA product. According to estimates, the function of about 40% or more of the transcripts is not known. Besides, there are regulatory elements in the genome, like promoter and enhancer, that coordinate and organize the gene expression (Nobrega et al., 2003; Poulin et al., 2005; Woolfe et al., 2005; Prabhakar et al., 2006; Pennacchio et al., 2006). Efforts are being made to identify such elements and establish their role in gene expression (Visel et al., 2009), the role of these sequences have not been fully explored. Genome-wide association studies CONTENTSOMICS: Biomedical Perspectives and Applications, Edited by Debmalya Barh, Kenneth Blum, Margaret Madigan, 11/2011; CRC Press., ISBN: 9781439850084
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ABSTRACT: Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain, and non-coding RNAs - and microRNAs (miRNAs) in particular - regulate both immune and neuronal processes. Specifically, miRNAs control macromolecular complexes in neurons, glia and immune cells and regulate signals used for neuro-immune communication in the pain pathway. Therefore, miRNAs may be hypothesized as critically important master switches modulating chronic pain. In particular, understanding the concerted function of miRNA in the regulation of nociception and endogenous analgesia and defining the importance of miRNAs in the circuitries and cognitive, emotional and behavioral components involved in pain is expected to shed new light on the enigmatic pathophysiology of neuropathic pain, migraine and complex regional pain syndrome. Specific miRNAs may evolve as new druggable molecular targets for pain prevention and relief. Furthermore, predisposing miRNA expression patterns and inter-individual variations and polymorphisms in miRNAs and/or their binding sites may serve as biomarkers for pain and help to predict individual risks for certain types of pain and responsiveness to analgesic drugs. miRNA-based diagnostics are expected to develop into hands-on tools that allow better patient stratification, improved mechanism-based treatment, and targeted prevention strategies for high risk individuals.Frontiers in Molecular Neuroscience 10/2013; 6:33. DOI:10.3389/fnmol.2013.00033
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ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is the most frequent psychiatric disorder in children, where it displays a global prevalence of 5 %. In up to 50 % of the cases, ADHD may persist into adulthood (aADHD), where it is often comorbid with personality disorders. Due to a potentially heritable nature of this comorbidity, we hypothesized that their genetic framework may contain common risk-modifying genes. SPOCK3, a poorly characterized, putatively Ca(2+)-binding extracellular heparan/chondroitin sulfate proteoglycan gene encoded by the human chromosomal region 4q32.3, was found to be associated with polymorphisms among the top ranks in a genome-wide association study (GWAS) on ADHD and a pooled GWAS on personality disorder (PD). We therefore genotyped 48 single nucleotide polymorphisms (SNPs) representative of the SPOCK3 gene region in 1,790 individuals (n aADHD = 624, n PD = 630, n controls = 536). In this analysis, we found two SNPs to be nominally associated with aADHD (rs7689440, rs897511) and four PD-associated SNPs (rs7689440, rs897511, rs17052671 and rs1485318); the latter even reached marginal significance after rigorous Bonferroni correction. Bioinformatics tools predicted a possible influence of rs1485318 on transcription factor binding, whereas the other candidate SNPs may have effects on alternative splicing. Our results suggest that SPOCK3 may modify the genetic risk for ADHD and PD; further studies are, however, needed to identify the underlying mechanisms.European Archives of Psychiatry and Clinical Neuroscience 11/2013; DOI:10.1007/s00406-013-0476-2 · 3.36 Impact Factor