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.

Machado Joseph disease is not an allele of the spinocerebellar ataxia 2 locus

Abstract: Machado Joseph disease (MJD) is a progressive, spinocerebellar ataxia (SCA) with an autosomal dominant mode of inheritance and almost complete penetrance. Clinically, it is difficult to distinguish it from other autosomal dominantly inherited ataxias, and it has been suggested that MJD may be caused by an allelic variant of SCA. Exclusion of MJD from the SCA1 locus on chromosome 6p has previously been demonstrated. However, following the recent assignment of a second locus for spinocerebellar ataxia (SCA2) to chromosome 12q in a large Cuban kindred of Spanish origin, we have investigated linkage in MJD families using the two markers, D12S58 and PLA2, that flank this disease gene. The MJD locus was definitively excluded from an interval spanning approximately 70 cM, which includes these loci. These studies demonstrate that MJD and SCA2 are genetically distinct despite similarities in disease phenotype and ancestral origins of the patients. Thus, the as yet unmapped MJD locus represents a third SCA locus, providing further evidence for genetic heterogeneity within these disorders.

Polygenic scores for major depressive disorder and depressive symptoms predict response to lithium in patients with bipolar disorder

Abstract: Background Lithium is a first-line medication for bipolar disorder (BD), but only ~30% of patients respond optimally to the drug. Since genetic factors are known to mediate lithium treatment response, we hypothesized whether polygenic susceptibility to the spectrum of depression traits is associated with treatment outcomes in patients with BD. In addition, we explored the potential molecular underpinnings of this relationship. Methods Weighted polygenic scores (PGSs) were computed for major depressive disorder (MDD) and depressive symptoms (DS) in BD patients from the Consortium on Lithium Genetics (ConLi + Gen; n=2,586) who received lithium treatment. Lithium treatment outcome was assessed using the ALDA scale. Summary statistics from genome-wide association studies (GWAS) in MDD (130,664 cases and 330,470 controls) and DS (n=161,460) were used for PGS weighting. Associations between PGSs of depression traits and lithium treatment response were assessed by binary logistic regression. We also performed a cross-trait meta-GWAS, followed by Ingenuity ® Pathway Analysis. Outcomes BD patients with a low polygenic load for depressive traits were more likely to respond well to lithium, compared to patients with high polygenic load (MDD: OR =1.64 [95%CI: 1.26-2.15], lowest vs highest PGS quartiles; DS: OR=1.53 [95%CI: 1.18-2.00]). Associations were significant for type 1, but not type 2 BD. Cross-trait GWAS and functional characterization implicated voltage-gated potassium channels, insulin-related pathways, mitogen-activated protein-kinase (MAPK) signaling, and miRNA expression. Interpretation Genetic loading to depression traits in BD patients lower their odds of responding optimally to lithium. Our findings support the emerging concept of a lithium-responsive biotype in BD. Funding See attached details

Epistasis analyses indicate association between cerebral amyloid deposition and genes involved in immuno-response

Abstract: groups had smaller thalamic volumes than non-carriers. No significant group differences were evident for other imaging measures. Conclusions: Lower thalamic volumes and altered diffusivity were evident in FAD MCs compared to non-carriers at a stage when whole brain volumes and atrophy rates were similar. Thalamic FA in particular merits further investigation as a marker of early disease progression in larger FAD cohorts.

Glucocerebrosidase activity in Parkinson disease with and without GBA mutations (S7.003)

Abstract: Importance: Glucocerebrosidase (GBA) mutations are associated with Parkinson’s disease (PD). Whether glucocerebrosidase enzymatic (GCase) activity in dried blood spots is lower in GBA carriers, and in PD cases compared to controls, is unknown. Objective: To measure glucocerebrosidase enzymatic (GCase) activity in dried blood spots in PD patients with and without GBA mutations and controls. Methods: PD patients (n=517) and controls (n=252) were recruited from Columbia University, and fully sequenced for GBA mutations. GCase activity in dried blood spot was measured by mass spectrometry-based assay. GCase activity was compared among carriers of two GBA mutations/variants (homozygotes and compound heterozygotes), GBA heterozygotes, and non-carriers. The association between GCase activity and PD status was measured in adjusted regression models excluding GBA and LRRK2 G2019S mutation carriers. In non-GBA non-LRKK2 PD patients, the association between GCase activity and disease characteristics was examined. Results: PD patients had slightly lower mean GCase activity than controls (11.14µmol/l/h versus 11.85µmol/l/h, p=0.011). GBA Homozygotes/Compound heterozygotes had lower GCase activity than GBA heterozygotes (0.85µmol/l/h versus 7.88µmol/l/h, p<0.001), and GBA heterozygotes had lower GCase activity than GBA and LRRK2 non-carriers (7.88µmol/l/h versus 11.93µmol/l/h, p<0.001). PD patients had lower GCase activity than controls even after exclusion of all GBA and LRRK2 carriers (11.53µmol/l/h, versus 12.11µmol/l/h, p=0.036) and adjustment for age and gender (p=0.012). However, LRRK2 G2019S carriers (n=36) had higher enzymatic activity than non-carriers (13.7µmol/l/h versus 11.93µmol/l/h, p=0.002). Among PD non-GBA non-LRRK2 carriers, higher GCase activity was associated with longer disease duration (p=0.002) in adjusted models, possibly indicating a milder disease course. Interpretation: Lower GCase activity is strongly associated GBA mutations and modestly with PD after excluding all carriers. High GCase activity in LRRK2 G2019S carriers may reflect a distinct pathogenic mechanism. Funding: Parkinson’s Disease Foundation, NIH (K02NS080915, NS036630 and UL1 TR000040) Disclosure: The NIH K02 NS080915. Parkinson9s Disease Foudnation: research support. Smart Foundation: research support and the Michael J Fox foundation: research support through the L Dr. Levy has nothing to disclose. Dr. Waters has received personal compensation for activities with UCB Pharma and Teva Neuroscience as a speaker. Dr. Fahn has received personal compensation for activities with Merz Pharmaceuticals. Dr. Ford has received personal compensation for activities with Johns Hopkins Medicine CME. Dr. Kuo has nothing to disclose. Dr. Mazzoni has nothing to disclose. Dr. Marder has received personal compensation in an editorial capacity for Current Neuroscience. Dr. Pauciulo has nothing to disclose. Dr. Nichols has nothing to disclose. Dr. Gan-Or has nothing to disclose. Dr. Rouleau has nothing to disclose. Dr. Chung has nothing to disclose. Dr. Wolf has received personal compensation for activities with Genzyme Corporation as an employee. Dr. Oliva has received personal compensation for activities with Genzyme as an employee. Dr. Keutzer has received personal compensation for activities with Sanofi as an employee. Dr. Zhang has received personal compensation for activities with Genzyme Corporation as an employee.

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.