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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.


Papers
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Journal Article
TL;DR: It is maintained that it is possible to use animal models to map genes or loci involved in behavioural traits that are relevant to schizophrenia and that these genes can be tested in patients with schizophrenia who have been carefully phenotyped for traits "isomorphic" to the ones modelled in mice.
Abstract: Genetic epidemiological studies strongly suggest that additive and interactive genes, each with small effects, mediate the genetic vulnerability for schizophrenia. With the human genome working draft at hand, candidate gene (and ultimately large-scale genome-wide) association studies are gaining renewed interest in the effort to unravel the complex genetics of schizophrenia. In the absence of an unequivocally established biological theory for schizophrenia, identifying candidate genes to be tested in an association paradigm remains a challenging task. We maintain that it is possible to use animal models to map genes or loci involved in behavioural traits that are relevant to schizophrenia. The human genes (or syntenic loci) homologous to those identified in mice can subsequently be tested in patients with schizophrenia who have been carefully phenotyped for traits “isomorphic” to the ones modelled in mice. If confirmed in humans, these genes may be further analyzed in the animal model to identify their role and the biological network they are involved in. To tackle the complex and intimidating problem of the genetics of schizophrenia, it may be necessary to go from animal models to human studies and vice versa; this strategy has been proven to be efficient in less complicated, though complex, human diseases.

29 citations

Journal ArticleDOI
TL;DR: A family based association study in a sample of French Canadian patients from Quebec showed a tendency for association in the comorbidity‐free subgroup, which may reflect the proximity of markers D7S522,D7S523, and possibly D7s1516 to a gene or regulatory region relevant to TS predisposition.
Abstract: Tourette syndrome (TS) is a complex neuropychiatric disorder with a strong genetic basis. Although no specific susceptibility genes have been identified for TS, cytogenetic studies in selected cases suggest the existence of a predisposing gene located in the 7q31 chromosomal region. In order to test the hypothesis of a possible relationship between this region and TS at the population level, we undertook a family based association study in a sample of French Canadian patients from Quebec. For this purpose, markers D7S522, D7S523, and D7S1516 were tested using the extended transmission disequilibrium test (e-TDT). Marker D7S522 showed a biased transmission of alleles from heterozygote parents to their TS offsprings (allele-wise TDT chi(2) = 12.61, 4 df, P = 0.013, genotype-wise TDT chi(2) = 15.49, 7 df, P = 0.030). When the analysis was restricted to patients without ADHD or OCD comorbidity, similar results were observed both allele and genotype-wise (chi(2) = 10.68, 4 df, P = 0.03 and chi(2) = 12.55, 5 df, P = 0.028, respectively). In addition, marker D7S523 was also associated (allele-wise TDT chi(2) = 18.37, 7 df, P = 0.01 and genotype-wise TDT chi(2) = 46.26, 17 df, P = 0.00016), and showed a tendency for association in the comorbidity-free subgroup (genotype-wise TDT chi(2) = 18.7, 10 df, P = 0.044). Finally, marker D7S1516, contained in the inner mitochondrial membrane peptidase 2 like (IMMP2L) gene, also showed a tendency for association (genotype-wise TDT chi(2) = 32.87, 21 df, P = 0.048). These results may reflect the proximity of markers D7S522, D7S523, and possibly D7S1516 to a gene or regulatory region relevant to TS predisposition.

29 citations

Journal ArticleDOI
TL;DR: The results of this pilot study showed that UES dilatation with Maloney bougie or achalasia dilator may be an effective treatment of moderate dysphagia in patients with OPMD, however, further studies with larger sample sizes are needed to corroborate these results and to assess long-term outcome.

29 citations

Posted ContentDOI
08 Jul 2016-bioRxiv
TL;DR: A European ancestry sample composed of 2,435 TS cases and 4,100 controls for copy-number variants using SNP microarrays was examined and identified two genome-wide significant loci that confer a substantial increase in risk for TS.
Abstract: Tourette syndrome (TS) is highly heritable, although identification of its underlying genetic cause(s) has remained elusive. We examined a European ancestry sample composed of 2,435 TS cases and 4,100 controls for copy-number variants (CNVs) using SNP microarrays and identified two genome-wide significant loci that confer a substantial increase in risk for TS (NRXN1, OR=20.3, 95%CI [2.6-156.2], p=6.0 × 10-6; CNTN6, OR=10.1, 95% CI [2.3-45.4], p=3.7 × 10-5). Approximately 1% of TS cases carried one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.

29 citations

Journal ArticleDOI
TL;DR: In a cohort of patients with young‐onset Parkinson's disease, the authors assessed the prevalence of genetic mutations in those who enrolled in deep brain stimulation (DBS) programs compared with those who did not enroll DBS programs.
Abstract: Objective In a cohort of patients with young-onset Parkinson's disease (PD), the authors assessed (1) the prevalence of genetic mutations in those who enrolled in deep brain stimulation (DBS) programs compared with those who did not enroll DBS programs and (2) specific genetic and clinical predictors of DBS enrollment. Methods Subjects were participants from 3 sites (Columbia University, Rush University, and the University of Pennsylvania) in the Consortium on Risk for Early Onset Parkinson's Disease (CORE-PD) who had an age at onset < 51 years. The analyses presented here focus on glucocerebrosidase (GBA), leucine-rich repeat kinase 2 (LRRK2), and parkin (PRKN) mutation carriers. Mutation carrier status, demographic data, and disease characteristics in individuals who did and did not enroll in DBS were analyzed. The association between mutation status and DBS placement was assessed in logistic regression models. Results Patients who had PD with either GBA, LRRK2, or PRKN mutations were more common in the DBS group (n = 99) compared with the non-DBS group (n = 684; 26.5% vs. 16.8%, respectively; P = 0.02). In a multivariate logistic regression model, GBA mutation status (odds ratio, 2.1; 95% confidence interval, 1.0–4.3; P = 0.05) was associated with DBS surgery enrollment. However, when dyskinesia was included in the multivariate logistic regression model, dyskinesia had a strong association with DBS placement (odds ratio, 3.8; 95% confidence interval, 1.9–7.3; P < 0.0001), whereas the association between GBA mutation status and DBS placement did not persist (P = 0.25). Conclusions DBS populations are enriched with genetic mutation carriers. The effect of genetic mutation carriers on DBS outcomes warrants further exploration.

29 citations


Cited by
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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

Journal ArticleDOI
01 Jun 1990-Cell
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

Journal ArticleDOI
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

Journal ArticleDOI
04 Mar 1993-Nature
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

Journal ArticleDOI
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