Professional Education

  • Doctor of Philosophy, McGill University (2023)
  • BSc, Vancouver Island University, Biology
  • PhD, McGill University, Human Genetics

Stanford Advisors

All Publications

  • Rare variant and polygenic analyses of amyotrophic lateral sclerosis in the French-Canadian genome. Genetics in medicine : official journal of the American College of Medical Genetics Ross, J. P., Akcimen, F., Liao, C., Kwan, K., Phillips, D. E., Schmilovich, Z., Spiegelman, D., Genge, A., Dupre, N., Dion, P. A., Farhan, S. M., Rouleau, G. A. 2023: 100967


    PURPOSE: The genetic etiology of amyotrophic lateral sclerosis (ALS) includes few rare, large-effect variants and potentially many common, small-effect variants per case. The genetic risk liability for ALS might require a threshold comprised of a certain amount of variants. Here, we tested the degree to which risk for ALS was affected by rare variants in ALS genes, polygenic risk score, or both.METHODS: 335 ALS cases and 356 controls from Quebec, Canada were concurrently tested by SNP-chip genotyping and targeted sequencing of ALS genes known at the time of study inception. ALS GWAS summary statistics were used to estimate an ALS polygenic risk score (PRS). Cases and controls were subdivided into rare variant heterozygotes and non-heterozygotes.RESULTS: Risk for ALS was significantly associated with PRS and rare variants independently in a logistic regression model. While ALS PRS predicted a small amount of ALS risk overall, the effect was most pronounced between ALS cases and controls that were not heterozygous for a rare variant in the ALS genes surveyed.CONCLUSION: Both PRS and rare variants in ALS genes impact risk for ALS. PRS for ALS is most informative when rare variants are not observed in ALS genes.

    View details for DOI 10.1016/j.gim.2023.100967

    View details for PubMedID 37638500

  • Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids. PLoS genetics Tamaki, Y., Ross, J. P., Alipour, P., Castonguay, C. É., Li, B., Catoire, H., Rochefort, D., Urushitani, M., Takahashi, R., Sonnen, J. A., Stifani, S., Dion, P. A., Rouleau, G. A. 2023; 19 (2): e1010606


    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by progressive loss of motor neurons and there is currently no effective therapy. Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein 43 kDa (TDP-43) within the CNS is a pathological hallmark in sporadic ALS and prion-like propagation of pathogenic TDP-43 is thought to be implicated in disease progression. However, cell-to-cell transmission of pathogenic TDP-43 in the human CNS has not been confirmed experimentally. Here we used induced pluripotent stem cells (iPSCs)-derived cerebral organoids as recipient CNS tissue model that are anatomically relevant human brain. We injected postmortem spinal cord protein extracts individually from three non-ALS or five sporadic ALS patients containing pathogenic TDP-43 into the cerebral organoids to validate the templated propagation and spreading of TDP-43 pathology in human CNS tissue. We first demonstrated that the administration of spinal cord extracts from an ALS patient induced the formation of TDP-43 pathology that progressively spread in a time-dependent manner in cerebral organoids, suggesting that pathogenic TDP-43 from ALS functioned as seeds and propagated cell-to-cell to form de novo TDP-43 pathology. We also reported that the administration of ALS patient-derived protein extracts caused astrocyte proliferation to form astrogliosis in cerebral organoids, reproducing the pathological feature seen in ALS. Moreover, we showed pathogenic TDP-43 induced cellular apoptosis and that TDP-43 pathology correlated with genomic damage due to DNA double-strand breaks. Thus, our results provide evidence that patient-derived pathogenic TDP-43 can mimic the prion-like propagation of TDP-43 pathology in human CNS tissue. Our findings indicate that our assays with human cerebral organoids that replicate ALS pathophysiology have a promising strategy for creating readouts that could be used in future drug discovery efforts against ALS.

    View details for DOI 10.1371/journal.pgen.1010606

    View details for PubMedID 36745687

    View details for PubMedCentralID PMC9934440

  • Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function. Stroke Roy, V., Ross, J. P., Pépin, R., Cortez Ghio, S., Brodeur, A., Touzel Deschênes, L., Le-Bel, G., Phillips, D. E., Milot, G., Dion, P. A., Guérin, S., Germain, L., Berthod, F., Auger, F. A., Rouleau, G. A., Dupré, N., Gros-Louis, F. 2022; 53 (4): 1263-1275


    Variants in the ring finger protein 213 (RNF213) gene are known to be associated with increased predisposition to cerebrovascular diseases development. Genomic studies have identified RNF213 as a major risk factor of Moyamoya disease in East Asian descendants. However, little is known about the RNF213 (ring finger protein 213) biological functions or its associated pathogenic mechanisms underlying Moyamoya disease.To investigate RNF213 loss-of-function effect in endothelial cell, stable RNF213-deficient human cerebral endothelial cells were generated using the CRISPR-Cas9 genome editing technology.In vitro assays, using RNF213 knockout brain endothelial cells, showed clear morphological changes and increased blood-brain barrier permeability. Downregulation and delocalization of essential interendothelial junction proteins involved in the blood-brain barrier maintenance, such as PECAM-1 (platelet endothelial cell adhesion molecule-1), was also observed. Brain endothelial RNF213-deficient cells also showed an abnormal potential to transmigration of leukocytes and secreted high amounts of proinflammatory cytokines.Taken together, these results indicate that RNF213 could be a key regulator of cerebral endothelium integrity, whose disruption could be an early pathological mechanism leading to Moyamoya disease. This study also further reinforces the importance of blood-brain barrier integrity in the development of Moyamoya disease and other RNF213-associated diseases.

    View details for DOI 10.1161/STROKEAHA.120.032691

    View details for PubMedID 34991336

  • Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nature genetics van Rheenen, W., van der Spek, R. A., Bakker, M. K., van Vugt, J. J., Hop, P. J., Zwamborn, R. A., de Klein, N., Westra, H. J., Bakker, O. B., Deelen, P., Shireby, G., Hannon, E., Moisse, M., Baird, D., Restuadi, R., Dolzhenko, E., Dekker, A. M., Gawor, K., Westeneng, H. J., Tazelaar, G. H., van Eijk, K. R., Kooyman, M., Byrne, R. P., Doherty, M., Heverin, M., Al Khleifat, A., Iacoangeli, A., Shatunov, A., Ticozzi, N., Cooper-Knock, J., Smith, B. N., Gromicho, M., Chandran, S., Pal, S., Morrison, K. E., Shaw, P. J., Hardy, J., Orrell, R. W., Sendtner, M., Meyer, T., Başak, N., van der Kooi, A. J., Ratti, A., Fogh, I., Gellera, C., Lauria, G., Corti, S., Cereda, C., Sproviero, D., D'Alfonso, S., Sorarù, G., Siciliano, G., Filosto, M., Padovani, A., Chiò, A., Calvo, A., Moglia, C., Brunetti, M., Canosa, A., Grassano, M., Beghi, E., Pupillo, E., Logroscino, G., Nefussy, B., Osmanovic, A., Nordin, A., Lerner, Y., Zabari, M., Gotkine, M., Baloh, R. H., Bell, S., Vourc'h, P., Corcia, P., Couratier, P., Millecamps, S., Meininger, V., Salachas, F., Mora Pardina, J. S., Assialioui, A., Rojas-García, R., Dion, P. A., Ross, J. P., Ludolph, A. C., Weishaupt, J. H., Brenner, D., Freischmidt, A., Bensimon, G., Brice, A., Durr, A., Payan, C. A., Saker-Delye, S., Wood, N. W., Topp, S., Rademakers, R., Tittmann, L., Lieb, W., Franke, A., Ripke, S., Braun, A., Kraft, J., Whiteman, D. C., Olsen, C. M., Uitterlinden, A. G., Hofman, A., Rietschel, M., Cichon, S., Nöthen, M. M., Amouyel, P., Traynor, B. J., Singleton, A. B., Mitne Neto, M., Cauchi, R. J., Ophoff, R. A., Wiedau-Pazos, M., Lomen-Hoerth, C., van Deerlin, V. M., Grosskreutz, J., Roediger, A., Gaur, N., Jörk, A., Barthel, T., Theele, E., Ilse, B., Stubendorff, B., Witte, O. W., Steinbach, R., Hübner, C. A., Graff, C., Brylev, L., Fominykh, V., Demeshonok, V., Ataulina, A., Rogelj, B., Koritnik, B., Zidar, J., Ravnik-Glavač, M., Glavač, D., Stević, Z., Drory, V., Povedano, M., Blair, I. P., Kiernan, M. C., Benyamin, B., Henderson, R. D., Furlong, S., Mathers, S., McCombe, P. A., Needham, M., Ngo, S. T., Nicholson, G. A., Pamphlett, R., Rowe, D. B., Steyn, F. J., Williams, K. L., Mather, K. A., Sachdev, P. S., Henders, A. K., Wallace, L., de Carvalho, M., Pinto, S., Petri, S., Weber, M., Rouleau, G. A., Silani, V., Curtis, C. J., Breen, G., Glass, J. D., Brown, R. H., Landers, J. E., Shaw, C. E., Andersen, P. M., Groen, E. J., van Es, M. A., Pasterkamp, R. J., Fan, D., Garton, F. C., McRae, A. F., Davey Smith, G., Gaunt, T. R., Eberle, M. A., Mill, J., McLaughlin, R. L., Hardiman, O., Kenna, K. P., Wray, N. R., Tsai, E., Runz, H., Franke, L., Al-Chalabi, A., Van Damme, P., van den Berg, L. H., Veldink, J. H. 2021; 53 (12): 1636-1648


    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

    View details for DOI 10.1038/s41588-021-00973-1

    View details for PubMedID 34873335

    View details for PubMedCentralID PMC8648564

  • Oligogenicity, C9orf72 expansion, and variant severity in ALS. Neurogenetics Ross, J. P., Leblond, C. S., Laurent, S. B., Spiegelman, D., Dionne-Laporte, A., Camu, W., Dupré, N., Dion, P. A., Rouleau, G. A. 2020; 21 (3): 227-242


    "Oligogenic inheritance" is used to describe cases where more than one rare pathogenic variant is observed in the same individual. While multiple variants can alter disease presentation, the necessity of multiple variants to instigate pathogenesis has not been addressed in amyotrophic lateral sclerosis (ALS). We sequenced ALS-associated genes in C9orf72-expansion-positive and negative ALS patients, alongside unaffected controls, to test the importance of oligogenicity and variant deleteriousness in ALS. We found that all groups had similar numbers of rare variants, but that variant severity was significantly higher in C9orf72-negative ALS cases, suggesting sufficiency of C9orf72 expansion to cause ALS alone.

    View details for DOI 10.1007/s10048-020-00612-7

    View details for PubMedID 32385536

  • Exome sequencing in genetic disease: recent advances and considerations. F1000Research Ross, J. P., Dion, P. A., Rouleau, G. A. 2020; 9


    Over the past decade, exome sequencing (ES) has allowed significant advancements to the field of disease research. By targeting the protein-coding regions of the genome, ES combines the depth of knowledge on protein-altering variants with high-throughput data generation and ease of analysis. New discoveries continue to be made using ES, and medical science has benefitted both theoretically and clinically from its continued use. In this review, we describe recent advances and successes of ES in disease research. Through selected examples of recent publications, we explore how ES continues to be a valuable tool to find variants that might explain disease etiology or provide insight into the biology underlying the disease. We then discuss shortcomings of ES in terms of variant discoveries made by other sequencing technologies that would be missed because of the scope and techniques of ES. We conclude with a brief outlook on the future of ES, suggesting that although newer and more thorough sequencing methods will soon supplant ES, its results will continue to be useful for disease research.

    View details for DOI 10.12688/f1000research.19444.1

    View details for PubMedID 32431803

    View details for PubMedCentralID PMC7205110

  • Evolution of a Human-Specific Tandem Repeat Associated with ALS. American journal of human genetics Course, M. M., Gudsnuk, K. n., Smukowski, S. N., Winston, K. n., Desai, N. n., Ross, J. P., Sulovari, A. n., Bourassa, C. V., Spiegelman, D. n., Couthouis, J. n., Yu, C. E., Tsuang, D. W., Jayadev, S. n., Kay, M. A., Gitler, A. D., Dupre, N. n., Eichler, E. E., Dion, P. A., Rouleau, G. A., Valdmanis, P. N. 2020


    Tandem repeats are proposed to contribute to human-specific traits, and more than 40 tandem repeat expansions are known to cause neurological disease. Here, we characterize a human-specific 69 bp variable number tandem repeat (VNTR) in the last intron of WDR7, which exhibits striking variability in both copy number and nucleotide composition, as revealed by long-read sequencing. In addition, greater repeat copy number is significantly enriched in three independent cohorts of individuals with sporadic amyotrophic lateral sclerosis (ALS). Each unit of the repeat forms a stem-loop structure with the potential to produce microRNAs, and the repeat RNA can aggregate when expressed in cells. We leveraged its remarkable sequence variability to align the repeat in 288 samples and uncover its mechanism of expansion. We found that the repeat expands in the 3'-5' direction, in groups of repeat units divisible by two. The expansion patterns we observed were consistent with duplication events, and a replication error called template switching. We also observed that the VNTR is expanded in both Denisovan and Neanderthal genomes but is fixed at one copy or fewer in non-human primates. Evaluating the repeat in 1000 Genomes Project samples reveals that some repeat segments are solely present or absent in certain geographic populations. The large size of the repeat unit in this VNTR, along with our multiplexed sequencing strategy, provides an unprecedented opportunity to study mechanisms of repeat expansion, and a framework for evaluating the roles of VNTRs in human evolution and disease.

    View details for DOI 10.1016/j.ajhg.2020.07.004

    View details for PubMedID 32750315