Author
Guy A. Rouleau
Other affiliations: Utrecht University, University of Helsinki, Université de Montréal ...read more
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.
Papers published on a yearly basis
Papers
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TL;DR: In this paper, the authors outline the links between lithium's therapeutic mode of action and posttranslational modifications (PTMs) of one, or many, proteins, and explore the putative mechanism of how it restores PTM homeostasis, and thereby cellular physiology.
4 citations
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TL;DR: The function of SYNE1 is thus critical in the maintenance of cerebellar structure in humans, and it is expected that this disease will be a common cause of middle-age-onset recessive ataxia worldwide.
4 citations
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01 Aug 2011
TL;DR: This chapter will focus on a recent hypothesis implicating de novo mutations in synaptic genes that rare, highly penetrant mutations affecting any of many different genes which code for synaptic molecules, and which are specific to single families, predispose to Autism.
Abstract: It has been almost half a century since Leo Kanner first described the clinical phenotype associated with Autism1. Since Kanner's descriptions, much effort has been devoted to understanding and identifying the factors which may contribute to Autism. It was not until the early 80’s that compelling evidence started to accumulate suggesting that Autism is a disorder of abnormal brain development. It is now generally accepted that both genetic and environmental factors are implicated in the etiology of this intriguing condition. In the current chapter, we will focus on the role of genetic factors involved in the pathogenesis of Autism. While multiple hypotheses have been proposed to account for the genetic origin of Autism, some have received more empirical support than others. While it is likely that more than one genetic mechanisms is involved in the pathogenesis of this disorder, this chapter will focus on a recent hypothesis implicating de novo mutations in synaptic genes. This hypothesis is based on the proposition that rare, highly penetrant mutations affecting any of many different genes which code for synaptic molecules, and which are specific to single families, predispose to Autism. Empirical lines of evidence for this hypothesis will be presented, along with examples, some of which are derived from work by our group.
4 citations
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Utrecht University1, University of Exeter2, University of Queensland3, Katholieke Universiteit Leuven4, University of Bristol5, Biogen Idec6, King's College London7, South London and Maudsley NHS Foundation Trust8, University of Milan9, University of Sheffield10, Queen's University Belfast11, Koç University12, University of Turin13, Hadassah Medical Center14, Hebrew University of Jerusalem15, François Rabelais University16, University of Limoges17, Rafael Advanced Defense Systems18, Carlos III Health Institute19, Montreal Neurological Institute and Hospital20, McGill University21, Royal Brisbane and Women's Hospital22, Fiona Stanley Hospital23, University of Notre Dame24, Murdoch University25, Concord Repatriation General Hospital26, Macquarie University27, University of Sydney28, Neuroscience Research Australia29, University of New South Wales30, University of Malta31, Royal Prince Alfred Hospital32, Bellvitge University Hospital33, Tel Aviv Sourasky Medical Center34, Tel Aviv University35, Instituto de Medicina Molecular36, University of Massachusetts Medical School37, Umeå University38, Trinity College, Dublin39, University of Cambridge40
TL;DR: In this paper, the authors presented a case-control study of DNA methylation for amyotrophic lateral sclerosis (ALS) using 10,462 samples (7,344 ALS patients and 3,118 controls) and identified a total of 45 differentially methylated positions annotated to 42 genes.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability of around 50%. DNA methylation patterns can serve as biomarkers of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study (EWAS) meta-analysis in 10,462 samples (7,344 ALS patients and 3,118 controls), representing the largest case-control study of DNA methylation for any disease to date. We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We show that DNA-methylation-based proxies for HDL-cholesterol, BMI, white blood cell (WBC) proportions and alcohol intake were independently associated with ALS. Integration of these results with our latest GWAS showed that cholesterol biosynthesis was causally related to ALS. Finally, we found that DNA methylation levels at several DMPs and blood cell proportion estimates derived from DNA methylation data, are associated with survival rate in patients, and could represent indicators of underlying disease processes.
4 citations
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TL;DR: Kolappa et al. as discussed by the authors made a case that optimising brain health not only leads to improved individual health but also provides broader tangible benefits in the form of social and economic advances to communities, countries, regions and globally.
4 citations
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28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组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�ly.
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。
18,940 citations
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TL;DR: A model for the genetic basis of colorectal neoplasia that includes the following salient features is presented, which may be applicable to other common epithelial neoplasms, in which tumors of varying stage are more difficult to study.
11,576 citations
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TL;DR: 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 is presented.
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.
10,056 citations
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TL;DR: 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 O–2 to O2 and H2O2 is reported.
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.
6,733 citations
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TL;DR: It is found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas, which 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 tumors.
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.
6,309 citations