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.

Genetics of REM Sleep Behavior Disorder

Abstract: Studies on the genetic basis of REM sleep behavior disorder (RBD) have emerged only recently, so we are just beginning to understand how genetics affect the risk for RBD and its progression to the different synucleinopathies—Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Of the two genes most commonly associated with PD, GBA, and LRRK2, it is clear that mutations in GBA are important risk factors for RBD, and LRRK2 mutations probably have no pathogenic role in RBD. Other genetic risk factors for PD and DLB such as single nucleotide polymorphisms in the MAPT, SNCA, APOE, SCARB2, and other genes have also been studied. This chapter will summarize the current knowledge on RBD genetics and will discuss future aspects for research and clinical management.

Multi-tissue probabilistic fine-mapping of transcriptome-wide association study identifies cis-regulated genes for miserableness

Abstract: Miserableness is a behavioural trait that is characterized by strong negative feelings in an individual. Although environmental factors tend to invoke miserableness, it is common to feel miserable ‘for no reason’, suggesting an innate, potential genetic component. Currently, little is known about the functional relevance of common variants associated with miserableness. To further characterize the trait, we conducted a transcriptome-wide association study (TWAS) on 373,733 individuals and identified 104 signals across brain tissue panels with 37 unique genes. Subsequent probabilistic fine-mapping prioritized 95 genes into 90%-credible sets. Amongst these prioritized hits, C7orf50 had the highest posterior inclusion probability of 0.869 in the brain cortex. Furthermore, we demonstrate that many GWAS hits for miserableness are driven by expression. To conclude, we successfully identified several genes implicated in miserableness and highlighted the power of TWAS to prioritize genes associated with a trait. Short summary The first transcriptome-wide association study of miserableness identifies many genes including c7orf50 implicated in the trait.

Genome-wide association study in FTD: divide to conquer

Abstract: www.thelancet.com/neurology Vol 13 July 2014 643 See Articles page 686 2 Hoglinger GU, Melhem NM, Dickson DW, et al. Identifi cation of common variants infl uencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 2011; 43: 699–705. 3 Boxer AL, Lang AE, Grossman M, et al, on behalf of the AL-108-231 Investigators. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014; published online May 27. http://dx.doi.org/10.1016/S14744422(14)70088-2. 4 Reiman EM, Langbaum JB, Fleisher AS. Alzheimer’s Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J Alzheimers Dis 2011; 26 (suppl 3): 321–29. 5 Sperling RA, Rentz DM, Johnson KA, et al. The A4 Study: stopping AD before symptoms begin? Sci Transl Med 2014; 6: 228fs13. 6 Morris JC, Aisen PS, Bateman RJ, et al. Developing an international network for Alzheimer research: the Dominantly Inherited Alzheimer Network. Clin Investig (Lond) 2012; 2: 975–84. 7 Crenshaw DG, Gottschalk WK, Lutz MW, et al. Using genetics to enable studies on the prevention of Alzheimer’s disease. Clin Pharmacol Ther 2013; 93: 177–85. 8 Food and Drug Administration. Guidance for industry Alzheimer’s disease: developing drugs for the treatment of early stage disease. Draft guidance. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 2013. 9 Alzforum. Research Roundtable. http://www.alz.org/research/funding/ alzheimers_research_roundtable.asp (accessed May 18, 2014). 10 Alzforum. Collaborative Umbrella CAPs Three Prevention Trial Initiatives http://www.alzforum.org/news/conference-coverage/collaborativeumbrella-caps-three-prevention-trial-initiatives (accessed May 18, 2014).

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.