Guy A. Rouleau

Bio: Guy A. Rouleau is an academic researcher from Montreal Neurological Institute and Hospital. The author has contributed to research in topics: Genome-wide association study & Amyotrophic lateral sclerosis. The author has an hindex of 129, co-authored 884 publications receiving 65892 citations. Previous affiliations of Guy A. Rouleau include Utrecht University & University of Helsinki.

Erratum: Corrigendum: Reduced transcriptional regulatory competence of the androgen receptor in X–linked spinal and bulbar muscular atrophy

Abstract: A. N. Mhatre, M. A. Trifiro, M. Kaufman, P. Kazemi-Esfarjani, D. Figlewicz, G. Rouleau & L. Pinsky Nature Genetics 5,184–188 (1993) The acknowledgements that appeared in this paper were incorrect. The acknowledgements that were part of this paper are printed below. Acknowledgements We are grateful to D.

Céphalées et sommeil: un survol diagnostique et un guide pour le clinicien

Abstract: Le sommeil est un etat physiologique et comportemental caracterise par une isolation partielle de l’environnement. Lors du sommeil, un evenement perturbateur comme la douleur peut provoquer une reaction de microeveil breve et inconsciente vers un reveil comportemental caracterise par une reactivation thalamocorticale complete et un niveau plus eleve de conscience. Le sommeil devient alors fragmente et les plaintes de douleur se trouvent souvent exacerbees. La continuite oscillatoire de 90–110 minutes, rythme ultradien du sommeil leger et profond (non-REM: rapid eye movement) vers le sommeil paradoxal (REM), est alors rompue. Chez un patient souffrant de cephalee, on observe trois periodes durant lesquelles surviennent les crises en relation avec le sommeil: 1) dans les heures avant l’initiation du sommeil, 2) durant et, 3) apres le sommeil. La cephalee de tension et la migraine, la cephalee de type hypnique, l’algie vasculaire de la face (cluster headache) et l’hemicrânie paroxystique chronique peuvent survenir en relation avec le sommeil. Soulignons que la cephalee du reveil est parfois associee a du bruxisme (serrement et grincement des dents), a un abus de medications antalgiques, a de l’hypertension, a un trouble de l’humeur ou a des reductions du flux respiratoire lors du sommeil. Les cephalees suite a un traumatisme crânien sont frequentes et causent de l’insomnie, des reveils subits et prematures et surtout des matins penibles avec delai de phase circadienne. Dans le contexte d’une cephalee survenant en relation avec l’insomnie ou la somnolence diurne, la recherche de troubles respiratoires du sommeil, d’intrusions sous forme de mouvements periodiques des membres ou de bruxisme est indiquee. La polygraphie peut etre effectuee en laboratoire ou en ambulatoire. La gestion de ces cephalees suit les grands principes de la medecine contemporaine tout en visant une hygiene du sommeil maximale par therapie cognitive et comportementale, le maintien d’un rythme circadien ideal, la prise de melatonine, la correction du phenomene respiratoire. La prise d’hypnotique ne semble pas un traitement de choix a long terme.

Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease

Abstract: Machado-Joseph disease (MJD/SCA3) is the most common form of dominantly inherited ataxia worldwide. The disorder is caused by an expanded CAG repeat in the ATXN3 gene. Past studies have revealed that the length of the expansion partly explains the disease age at onset (AO) variability of MJD, which is confirmed in this study. Using a total of 786 MJD patients from five different geographical origins, a genome-wide association study (GWAS) was conducted to identify additional AO modifying factors that could explain some of the residual AO variability. We identified nine suggestively associated loci (P

Transcriptome-wide association study reveals increased neuronal FLT3 expression is associated with Tourette’s syndrome

Abstract: Tourette's Syndrome (TS) is a neurodevelopmental disorder that is characterized by motor and phonic tics. A recent TS genome-wide association study (GWAS) identified a genome-wide significant locus. However, determining the biological mechanism of GWAS signals remains difficult. To characterize effects of expression quantitative trait loci (eQTLs) in TS and understand biological underpinnings of the disease. Here, we conduct a TS transcriptome-wide association study (TWAS) consisting of 4819 cases and 9488 controls. We demonstrate that increased expression of FLT3 in the dorsolateral prefrontal cortex (DLPFC) is associated with TS. We further show that there is global dysregulation of FLT3 across several brain regions and probabilistic causal fine-mapping of the TWAS signal prioritizes FLT3 with a posterior inclusion probability of 0.849. After, we proxy the expression with 100 lymphoblastoid cell lines, and demonstrate that TS cells has a 1.72 increased fold change compared to controls. A phenome-wide association study also points toward FLT3 having links with immune-related pathways such as monocyte count. We further identify several splicing events in MPHOSPH9, CSGALNACT2 and FIP1L1 associated with TS, which are also implicated in immune function. This analysis of expression and splicing begins to explore the biology of TS GWAS signals.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

A framework for variation discovery and genotyping using next-generation DNA sequencing data

Abstract: Recent advances in sequencing technology make it possible to comprehensively catalogue genetic variation in population samples, creating a foundation for understanding human disease, ancestry and evolution. The amounts of raw data produced are prodigious and many computational steps are required to translate this output into high-quality variant calls. We present a unified analytic framework to discover and genotype variation among multiple samples simultaneously that achieves sensitive and specific results across five sequencing technologies and three distinct, canonical experimental designs. Our process includes (1) initial read mapping; (2) local realignment around indels; (3) base quality score recalibration; (4) SNP discovery and genotyping to find all potential variants; and (5) machine learning to separate true segregating variation from machine artifacts common to next-generation sequencing technologies. We discuss the application of these tools, instantiated in the Genome Analysis Toolkit (GATK), to deep whole-genome, whole-exome capture, and multi-sample low-pass (~4×) 1000 Genomes Project datasets.

Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis

Abstract: Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord. Its cause is unknown and it is uniformly fatal, typically within five years. About 10% of cases are inherited as an autosomal dominant trait, with high penetrance after the sixth decade. In most instances, sporadic and autosomal dominant familial ALS (FALS) are clinically similar. We have previously shown that in some but not all FALS pedigrees the disease is linked to a genetic defect on chromosome 21q (refs 8, 9). Here we report tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O2.- to O2 and H2O2 (ref. 10). Given this linkage and the potential role of free radical toxicity in other neurodenegerative disorders, we investigated SOD1 as a candidate gene in FALS. We identified 11 different SOD1 missense mutations in 13 different FALS families.

Genetic alterations during colorectal-tumor development.

Abstract: Because most colorectal carcinomas appear to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18) in 172 colorectal-tumor specimens representing various stages of neoplastic development. The specimens consisted of 40 predominantly early-stage adenomas from 7 patients with familial adenomatous polyposis, 40 adenomas (19 without associated foci of carcinoma and 21 with such foci) from 33 patients without familial polyposis, and 92 carcinomas resected from 89 patients. We found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas. However, ras mutations were found in only 9 percent of adenomas under 1 cm in size. Sequences on chromosome 5 that are linked to the gene for familial adenomatous polyposis were not lost in adenomas from the patients with polyposis but were lost in 29 to 35 percent of adenomas and carcinomas, respectively, from other patients. A specific region of chromosome 18 was deleted frequently in carcinomas (73 percent) and in advanced adenomas (47 percent) but only occasionally in earlier-stage adenomas (11 to 13 percent). Chromosome 17p sequences were usually lost only in carcinomas (75 percent). The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors. These results are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis.