We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 cases, 118,538 controls) from ethnically-diverse populations. We identified five new asthma loci, uncovered two additional novel associations at two known asthma loci, established asthma associations at two loci implicated previously in comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. Enrichment of asthma risk loci in enhancer marks, especially in immune cells, suggests a major role of these loci in the regulation of immune-related mechanisms.

Motivation: For the biologist, running bioinformatics analyses involves a time-consuming management of data and tools. Users need support to organize their work, retrieve parameters and reproduce their analyses. They also need to be able to combine their analytic tools using a safe data flow software mechanism. Finally, given that scientific tools can be difficult to install, it is particularly helpful for biologists to be able to use these tools through a web user interface. However, providing a web interface for a set of tools raises the problem that a single web portal cannot offer all the existing and possible services: it is the user, again, who has to cope with data copy among a number of different services. A framework enabling portal administrators to build a network of cooperating services would therefore clearly be beneficial.Results: We have designed a system, Mobyle, to provide a flexible and usable Web environment for defining and running bioinformatics analyses. It embeds simple yet powerful data management features that allow the user to reproduce analyses and to combine tools using a hierarchical typing system. Mobyle offers invocation of services distributed over remote Mobyle servers, thus enabling a federated network of curated bioinformatics portals without the user having to learn complex concepts or to install sophisticated software. While being focused on the end user, the Mobyle system also addresses the need, for the bioinfomatician, to automate remote services execution: PlayMOBY is a companion tool that automates the publication of BioMOBY web services, using Mobyle program definitions.Availability: The Mobyle system is distributed under the terms of the GNU GPLv2 on the project web site (http://bioweb2.pasteur.fr/projects/mobyle/). It is already deployed on three servers: http://mobyle.pasteur.fr, http://mobyle.rpbs.univ-paris-diderot.fr and http://lipm-bioinfo.toulouse.inra.fr/Mobyle. The PlayMOBY companion is distributed under the terms of the CeCILL license, and is available at http://lipm-bioinfo.toulouse.inra.fr/biomoby/PlayMOBY/.Contact: mobyle-support@pasteur.fr; mobyle-support@rpbs.univ-paris-diderot.fr; letondal@pasteur.frSupplementary information:Supplementary data are available at Bioinformatics online.

Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the E1-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure. In Caenorhabditis elegans, knockout of uba-5 and of human orthologous genes in the UFM1 cascade alter cholinergic, but not glutamatergic, neurotransmission. In addition, uba5 silencing in zebrafish decreased motility while inducing abnormal movements suggestive of seizures. These clinical, biochemical, and experimental findings support our finding of UBA5 mutations as a pathophysiological cause for early-onset encephalopathies due to abnormal protein ufmylation.