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.

The Project MinE databrowser: bringing large-scale whole-genome sequencing in ALS to researchers and the public.

Abstract: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative disease affecting 1 in 350 people. The aim of Project MinE is to elucidate the pathophysiology of ALS through whole-genome sequencing at least 15,000 ALS patients and 7,500 controls at 30X coverage. Here, we present the Project MinE data browser (databrowser.projectmine.com), a unique and intuitive one-stop, open-access server that provides detailed information on genetic variation analyzed in a new and still growing set of 4,366 ALS cases and 1,832 matched controls. Through its visual components and interactive design, the browser specifically aims to be a resource to those without a biostatistics background and allow clinicians and preclinical researchers to integrate Project MinE data into their own research. The browser allows users to query a transcript and immediately access a unique combination of detailed (meta)data, annotations and association statistics that would otherwise require analytic expertise and visits to scattered resources.

Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects

Abstract: Abstract Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2 . Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention.

Rare variants in complex traits: novel identification strategies and the role of de novo mutations.

Abstract: Following the limited success of linkage and association studies aimed at identifying the genetic causes of common neurodevelopmental syndromes like autism and schizophrenia, complex traits such as these have recently been considered under the 'common disease-rare variant' hypothesis. Prior to this hypothesis, the study of candidate genes has enabled the discovery of rare variants in complex disorders, and in turn some of these variants have highlighted the genetic contribution of de novo variants. De novo variants belong to a subcategory of spontaneous rare variants that are largely associated with sporadic diseases, which include some complex psychiatric disorders where the affected individuals do not transmit the genetic defects they carry because of their reduced reproductive fitness. Interestingly, recent studies have demonstrated the rate of germline de novo mutations to be higher in individuals with complex psychiatric disorders by comparison to what is seen in unaffected control individuals; moreover, de novo mutations carried by affected individuals have generally been more deleterious than those observed in control individuals. Advanced sequencing technologies have recently enabled the undertaking of massive parallel sequencing projects that can cover the entire coding sequences (exome) or genome of several individuals at once. Such advances have thus fostered the emergence of novel genetic hypotheses and ideas to investigate disease-causative genetic variations. The genetic underpinnings of a number of sporadic complex diseases is now becoming partly explained and more major breakthroughs for complex traits genomics should be expected in the near future.

Genome-wide TDT analysis in French-Canadian families with Tourette syndrome.

Abstract: Tourette syndrome (TS) is a complex neurodevelopmental disorder with an estimated prevalence of 1%1 that is characterized by motor and vocal tics as well as psychiatric comorbidities, such as obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD).2-4 Despite a strong genetic contribution,5,6 no common variants have been clearly associated with the disorder, possibly because of allelic and non-allelic genetic heterogeneity. Several candidate genes involved in dopaminergic neurotransmission have been analyzed based on the observation that neuroleptics are used to treat TS patients. Positive association results between TS and some of these genes have been reported.7-9 However, because other studies failed to replicate these results, the role played by dopaminergic in TS remains unclear.10-12 Founder populations are known to offer several advantages for the gene-mapping of complex traits, as the reduced genetic heterogeneity of population isolates is thought to simplify the genetic background of complex traits and higher frequencies of specific mutations inherited from a common ancestor may be observed. Moreover, even if the number of implicated genes is not decreased, the allelic heterogeneity is decreased and the presence of a common haplotype that segregates among patients is more probable than within a heterogeneous population.13 For instance, the G2019S substitution in the LRRK2 gene accounts for 20–40% of NorthAfrican Arab and Ashkenazi patients with Parkinson disease.14,15 In the French-Canadian (FC) population, founder mutations in the BRCA1 and BRCA2 genes were identified in 40% of patients from families with a high risk of breast and ovarian cancer.16 For several reasons, the FC population of Quebec displays all the characteristics of a population isolate. An estimated 2,600 pioneers who settled in Quebec before 1680 account for two thirds of the modern FC gene pool and a vast majority of FC people have, as ancestors, approximately 7,000 individuals who immigrated to Quebec before 1760. Given that these founders rarely mixed with other immigrants over three centuries and that there was a sustained demographic growth in the FC population, the ~6 million FC individuals currently living in Quebec inherited most of their genes from a relatively small pool of founders.17 Based on a cohort of 217 FC trios (father, mother and proband) presenting with TS, the goal of this study was to assess the presence of frequent and highly penetrant alleles predisposing to TS in the FC population. Affected individuals and their relatives were recruited through the Montreal General Genome-Wide TDTAnalysis in French-Canadian Families with Tourette Syndrome

A founder effect in three large Newfoundland families with a novel clinically variable spastic ataxia and supranuclear gaze palsy.

Abstract: A distinctive slowly progressive neurodegenerative disorder, which falls under a new category of neurological diseases, the hereditary spastic ataxias (HSA), is described in three independently ascertained Newfoundland kindreds. HSA is a heterogeneous group of disorders in which pyramidal tract features overlap cerebellar characteristics. The families are assumed to have the same condition as, although apparently unrelated, all originate in a historically isolated cluster of rural communities and link to the same locus at 12p13, SAX1. Clinically the phenotype is very variable but lower limb hypertonicity and hyperreflexia are early and prominent generally preceded by eye movement abnormality, an impaired vertical downward saccade and a typical involuntary head jerk. These are followed by variable levels of ataxia, dysarthria, and dysphagia. Onset occurs in the first two decades and can be detected in most by early adulthood. Significant mobility problems are present by the fourth decade with a broad based ataxic and spastic gait. MRI scans of brain and spinal cord were normal. Neuropathology showed degeneration of corticospinal tracts and posterior columns and midbrain neuronal loss. The phenotype is striking in its diversity among and within families and the variability of expression can be observed within the same sibship. Pedigree analysis shows no evidence of anticipation or any sex differences in severity. The condition is unusually prevalent in the province of Newfoundland, which is characteristic of a founder effect followed by isolation and large family size. Fine mapping efforts have reduced the critical interval of the SAX1 locus to 1.9Mb. Identification of the SAX1 gene will help to clarify the pathogenesis of this type of HSA.

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.