Biology subjects

Dubois, B.

Publications and source records attributed to Dubois, B..

3 recordsLinked to original sources

bioRxiv2018

Low frequency and rare coding variation contributes to multiple sclerosis risk

Multiple sclerosis is a common, complex neurological disease, where almost 20% of risk heritability can be attributed to common genetic variants, including >230 identified by genome-wide association studies (Patsopoulos et al., 2017). Multiple strands of evidence suggest that the majority of the remaining heritability is also due to the additive effects of individual variants, rather than epistatic interactions between these variants, or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that as much as 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common variant signals, which highlight a key role for regulatory T cell homeostasis and regulation, IFN{gamma} biology and NF{kappa}B signaling in MS pathogenesis. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.

genetics↗

bioRxiv2017

"A mosquito bites and a butterfly flies": a specific response type of frontal patients in a similarity task

BackgroundPatients with neurodegenerative diseases affecting the frontal lobes have difficulties in categorization tasks, such as the similarity tasks. They give two types of unusual response to the question: \"In what way are an orange and a banana alike?\", either a differentiation (\"one is yellow, the other is orange\") or a concrete similarity (\"they are sweet\").\n\nObjectiveTo characterize the categorization deficit of frontal patients and develop a short diagnostic tool to assess the nature of these difficulties.\n\nMethodWe analyzed the responses provided by frontal and non-frontal neurodegenerative patients in a novel verbal similarity task (SimiCat). We included 40 frontal patients with behavioral variant fronto-temporal dementia (bvFTD) and progressive supranuclear palsy (PSP), 23 patients with Alzheimers disease (AD) and 41 healthy matched controls. Responses that did not correspond to the expected taxonomic category (e.g.: fruits) were considered as errors.\n\nResultsAll patients groups were impaired at the SimiCat test compared to controls. Differentiation errors were specific of frontal patients. Receiver operating characteristic analyses showed that a cut-off of two differentiation errors or more achieved 85% sensitivity of 100% specificity to discriminate bvFTD from AD. A short version of the test (<5 min) showed similar discriminative validity as the full version.\n\nConclusionDifferentiation responses were specific of frontal patients. The SimiCat demonstrates good discriminative validity to differentiate bvFTD and AD. The short version of the test is a promising diagnostic tool that will need validation in future studies.

neuroscience↗

bioRxiv2017

The Multiple Sclerosis Genomic Map: Role of peripheral immune cells and resident microglia in susceptibility

AbstractWe assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain - resident immune cells. Thus, while MS is most likely initially triggered by perturbation of peripheral immune responses the functional responses of microglia and other brain cells are also altered and may have a role in targeting an autoimmune process to the central nervous system.\n\nOne Sentence SummaryWe report a detailed genetic and genomic map of multiple sclerosis, and describe the role of putatively affected genes in the peripheral immune system and brain resident microglia.

genetics↗