Jay Ross

All Publications

• Generation of two iPSC lines from ALS patients harboring C9orf72 hexanucleotide repeat expansions. Stem cell research Wu, D., Kojic, A., Ross, J. P., Li, D., Walther, P., Goyal, N., Sampson, J., Wu, J. C. 2026; 95: 104085

  Abstract

  The GGGGCC hexanucleotide repeat expansion (HRE) within the C9orf72 gene constitutes the leading genetic driver of amyotrophic lateral sclerosis (ALS). This fatal neurodegenerative disorder is characterized by the systematic loss of both the upper and lower motor neurons across both the central and peripheral nervous systems. This work describes the successful reprogramming of two human induced pluripotent stem cell (iPSC) lines originating from two independent ALS patients, both of whom carry a C9orf72 HRE mutation. Validation of the two established iPSC lines confirmed the expression of pluripotency markers, normal karyotypes, and successful trilineage differentiation. Consequently, these lines provide a robust in vitro platform to model ALS and study C9orf72-mediated disease mechanisms.

  View details for DOI 10.1016/j.scr.2026.104085

  View details for PubMedID 42648119

• Consequences of the Novel ALS-Associated <i>KIF5A</i> Variant c.2993-6C > A for Exon 27 Splicing and Axonal Transport of SFPQ NEUROLOGY-GENETICS Rouleau, G. A., Yu, Z., Ross, J. P., Rochefort, D., Li, B., Bornais, K., Chum, M., Farhan, S. M. K., Dion, P. A. 2026; 12 (2): e200362

  Abstract

  Recent studies have identified variants in the kinesin family member 5A (KIF5A) gene that predispose to amyotrophic lateral sclerosis (ALS). These ALS-linked KIF5A variants lead to the exclusion of exon 27, resulting in the production of a mutated protein with an altered C-terminal region (KIF5A ΔExon27). Through whole genome sequencing, we identified a novel KIF5A intronic variant, rs1057522322 (c.2993-6C > A; chr12:57582596C > A, GRCh38.p14), in a family segregating ALS. Our goal is to investigate the effect of this variant on exon 27 splicing and to assess its functional consequences on KIF5A-mediated cargo transport.Induced pluripotent stem cells (iPSCs) were generated from siblings with and without the c.2993-6C > A variant. RT-PCR was performed on RNA extracted from iPSC-derived neurons to assess exon 27 splicing. Functional studies were conducted on iPSC-derived motor neurons (MNs).RT-PCR confirmed that the c.2993-6C > A variant induced exon 27 skipping in KIF5A. Immunofluorescent staining showed that KIF5A ΔExon27 abolished the axonal interaction with splicing factor proline- and glutamine-rich, a cargo specifically transported by KIF5A. Under stress conditions, MNs carrying the c.2993-6C > A variant exhibited TDP-43 proteinopathy.KIF5A intronic variant c.2993-6C > A could be a risk factor for ALS. KIF5A ΔExon27 impairs KIF5A-mediated cargo transport and contributes to ALS pathogenesis in a TDP-43-dependent manner.

  View details for DOI 10.1212/NXG.0000000000200362

  View details for Web of Science ID 001714053400001

  View details for PubMedID 41836882

  View details for PubMedCentralID PMC12983328

• KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS. JCI insight Akiyama, T., Zeng, Y., Guo, C., Gautier, O., Koepke, L., Lyons, H., Molotsky, E., Bombosch, J. S., Sianto, O., Ross, J. P., Hoang, P., Zhao, L., Spencer, C., Sumner, C. J., Monje, M., Day, J. W., Gitler, A. D. 2026

  Abstract

  Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene leading to decreased SMN protein levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. SMN deficiency resulted in downregulation of kinesin heavy chain isoform 5A (KIF5A) in human neurons and in a mouse model of SMA. SMN associated with KIF5A mRNA and contributed to its stability. Reduced SMN levels impaired axon regeneration, which was rescued by KIF5A overexpression. Because KIF5A has also been connected to ALS, these findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as an SMN regulated factor. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.

  View details for DOI 10.1172/jci.insight.197941

  View details for PubMedID 41885937

• Copy Number Variant Duplications Associated with Essential Tremor TREMOR AND OTHER HYPERKINETIC MOVEMENTS Medeiros, M., Liao, C., Dilliott, A. A., Ross, J. P., Vuokila, V., Aboasali, F., Castonguay, C., Spiegelman, D., Hopfner, F., Vilarino-guell, C., Garcia-martin, E., Alonso-navarro, H., Agundez, J. A. G., Jimenez-jimenez, F., Pastor, P., Rajput, A., Rajput, A., Deuschl, G., Kuhlenbaumer, G., Girard, S. L., Farhan, S. M. K., Dion, P. A., Rouleau, G. A. 2026; 16: 10

  Abstract

  Essential tremor (ET) is a complex neurological disorder with a strong genetic basis, yet there remains a disparity between its estimated heritability and currently known genetic risk. This missing heritability has led to a lack of appropriate treatments and has exacerbated the misdiagnosis of patients.To address the missing heritability of ET, we called copy number variants (CNVs) in a large cohort of ET patients (n = 1,853) and unaffected controls (n = 10,336). CNVs were called from single nucleotide polymorphism (SNP) microarray data using PennCNV and QuantiSNP and only rare CNVs (frequency < 1%) intersecting protein coding regions of the genome were analyzed. To investigate whether CNV occurrence was associated with ET, global burden, pathogenicity burden, gene set enrichment, and gene burden tests were conducted.Global duplication burden by CNV number, CNV length, and number of genes affected by CNVs were all significantly elevated in ET patients compared to controls. Across gene-sets, duplications affecting Mendeliome genes, genes highly expressed in the brain, and genes expressed in the cerebellum were significantly enriched in patients compared to controls. Gene-based burden testing indicated that duplications involving ZNF813 were significantly less frequent in ET patients than in controls. No associations with deletion events were observed.Our results point to rare copy number duplications affecting protein coding regions of the genome as likely contributors to ET genetic risk. However, specific susceptibility genes could not be reliably identified, highlighting the need for larger studies of diverse variant types to clarify the genetic architecture of ET.

  View details for DOI 10.5334/tohm.1132

  View details for Web of Science ID 001693555800001

  View details for PubMedID 41694793

  View details for PubMedCentralID PMC12904121

• Polyserine likes the tau and not the label. Neuron Ross, J. P., Gitler, A. D. 2025; 113 (21): 3495-3497

  Abstract

  Aggregation of the protein tau is a feature of several neurodegenerative diseases. In this issue of Neuron, Van Alstyne et al. report a polyserine-motif-based strategy to target aggregation inhibitor proteins to tau aggregates, reducing pathology and rescuing neurodegeneration in animal models.

  View details for DOI 10.1016/j.neuron.2025.09.019

  View details for PubMedID 41197606

• KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS. bioRxiv : the preprint server for biology Akiyama, T., Zeng, Y., Guo, C., Gautier, O., Koepke, L. S., Bombosch, J., Sianto, O., Ross, J. P., Hoang, P. T., Zhao, L. Y., Spencer, C., Monje, M., Day, J. W., Gitler, A. D. 2025

  Abstract

  Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, leading to decreased SMN levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. Here, we demonstrate that SMN deficiency results in downregulation of KIF5A in human neurons and in a mouse model of SMA. We provide evidence that reduced SMN levels impair axon regeneration, which is rescued by KIF5A overexpression and that the RNA-binding protein SMN functions to stabilize KIF5A mRNA. These findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as a new SMN target. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.

  View details for DOI 10.1101/2025.07.11.664426

  View details for PubMedID 40672150

  View details for PubMedCentralID PMC12265700

• 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

  Abstract

  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

  Abstract

  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

• Transcriptomic effects of propranolol and primidone converge on molecular pathways relevant to essential tremor NPJ GENOMIC MEDICINE Castonguay, C., Liao, C., Khayachi, A., Liu, Y., Medeiros, M., Houle, G., Ross, J. P., Dion, P. A., Rouleau, G. A. 2022; 7 (1): 46

  Abstract

  Essential tremor (ET) is one of the most common movement disorders, affecting nearly 5% of individuals over 65 years old. Despite this, few genetic risk loci for ET have been identified. Recent advances in pharmacogenomics have previously been useful to identify disease related molecular targets. Notably, gene expression has proven to be quite successful for the inference of drug response in cell models. We sought to leverage this approach in the context of ET where many patients are responsive to two drugs: propranolol and primidone. In this study, cerebellar DAOY and neural progenitor cells were treated for 5 days with clinical concentrations of propranolol and primidone, after which RNA-sequencing was used to identify convergent differentially expressed genes across treatments. Propranolol was found to affect the expression of genes previously associated with ET and other movement disorders such as TRAPPC11. Pathway enrichment analysis of these convergent drug-targeted genes identified multiple terms related to calcium signaling, endosomal sorting, axon guidance, and neuronal morphology. Furthermore, genes targeted by ET drugs were enriched within cell types having high expression of ET-related genes in both cortical and cerebellar tissues. Altogether, our results highlight potential cellular and molecular mechanisms associated with tremor reduction and identify relevant genetic biomarkers for drug-responsiveness in ET.

  View details for DOI 10.1038/s41525-022-00318-9

  View details for Web of Science ID 000836236600001

  View details for PubMedID 35927430

  View details for PubMedCentralID PMC9352876

• Questioning the Association of the <i>STMN2</i> Dinucleotide Repeat With Amyotrophic Lateral Sclerosis NEUROLOGY-GENETICS Ross, J. P., Akcimen, F., Liao, C., Spiegelman, D., Weisburd, B., Dupre, N., Dion, P. A., Rouleau, G. A., Farhan, S. M. K. 2022; 8 (4): e678

  Abstract

  Recently, the number of dinucleotide CA repeats in an intron of the STMN2 gene was reported to be associated with an increased risk for amyotrophic lateral sclerosis (ALS). Therefore, we sought to replicate this observation in an independent group of ALS patients and a much larger control group.Here, we used whole-genome sequencing and tested the STMN2 CA repeat in a case-control cohort of the European genetic background and in genomes from various populations in the gnomAD cohort to attempt to replicate this proposed association.We find that repeats well above the previously reported pathogenic threshold of 19 are commonly observed in unaffected individuals across different populations. Furthermore, we did not observe an association between longer STMN2 CA repeats and ALS phenotype.In summary, our results do not support a role of STMN2 CA repeats toward ALS risk. As TDP-43 aggregation is central to ALS pathogenesis, lowered expression of STMN2 could be used as a biomarker for ALS. Therefore, a variant associated both with the risk for ALS and the level of STMN2 expression would be clinically useful. However, for a variant to be actionable, it must be strongly replicated in independent cohorts and exceed the rigorous statistical thresholds applied.

  View details for DOI 10.1212/NXG.0000000000000678

  View details for Web of Science ID 000837513900007

  View details for PubMedID 35923349

  View details for PubMedCentralID PMC9342143

• The value of testing for <i>ATXN2</i> intermediate repeat expansions in routine clinical practice for amyotrophic lateral sclerosis EUROPEAN JOURNAL OF HUMAN GENETICS Salmon, K., Ross, J. P., Bertone, V., Gobbo, M., Anoja, N., Karamchandani, J., Dion, P. A., Rouleau, G. A., Genge, A. 2022; 30 (11): 1205-1207

  View details for DOI 10.1038/s41431-022-01146-2

  View details for Web of Science ID 000828461500001

  View details for PubMedID 35864146

  View details for PubMedCentralID PMC9626461

• 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

  Abstract

  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

• Transcriptome-wide association study reveals increased neuronal <i>FLT3</i> expression is associated with Tourette's syndrome COMMUNICATIONS BIOLOGY Liao, C., Vuokila, V., Catoire, H., Akcimen, F., Ross, J. P., Bourassa, C. V., Dion, P. A., Meijer, I. A., Rouleau, G. A. 2022; 5 (1): 289

  Abstract

  Tourette's Syndrome (TS) is a neurodevelopmental disorder that is characterized by motor and phonic tics. A recent TS genome-wide association study (GWAS) identified a genome-wide significant locus. However, determining the biological mechanism of GWAS signals remains difficult. To characterize effects of expression quantitative trait loci (eQTLs) in TS and understand biological underpinnings of the disease. Here, we conduct a TS transcriptome-wide association study (TWAS) consisting of 4819 cases and 9488 controls. We demonstrate that increased expression of FLT3 in the dorsolateral prefrontal cortex (DLPFC) is associated with TS. We further show that there is global dysregulation of FLT3 across several brain regions and probabilistic causal fine-mapping of the TWAS signal prioritizes FLT3 with a posterior inclusion probability of 0.849. After, we proxy the expression with 100 lymphoblastoid cell lines, and demonstrate that TS cells has a 1.72 increased fold change compared to controls. A phenome-wide association study also points toward FLT3 having links with immune-related pathways such as monocyte count. We further identify several splicing events in MPHOSPH9, CSGALNACT2 and FIP1L1 associated with TS, which are also implicated in immune function. This analysis of expression and splicing begins to explore the biology of TS GWAS signals.

  View details for DOI 10.1038/s42003-022-03231-0

  View details for Web of Science ID 001027842200001

  View details for PubMedID 35354918

  View details for PubMedCentralID PMC8967882

• Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS SCIENCE TRANSLATIONAL MEDICINE Hop, P. J., Zwamborn, R. A. J., Hannon, E., Shireby, G. L., Nabais, M. F., Walker, E. M., van Rheenen, W., van Vugt, J. A., Dekker, A. M., Westeneng, H., Tazelaar, G. H. P., van Eijk, K. R., Moisse, M., Baird, D., Al Khleifat, A., Iacoangeli, A., Ticozzi, N., Ratti, A., Cooper-Knock, J., Morrison, K. E., Shaw, P. J., Basak, A., Chio, A., Calvo, A., Moglia, C., Canosa, A., Brunetti, M., Grassano, M., Gotkine, M., Lerner, Y., Zabari, M., Vourc'h, P., Corcia, P., Couratier, P., Pardina, J., Salas, T., Dion, P., Ross, J. P., Henderson, R. D., Mathers, S., McCombe, P. A., Needham, M., Nicholson, G., Rowe, D. B., Pamphlett, R., Mather, K. A., Sachdev, P. S., Furlong, S., Garton, F. C., Henders, A. K., Lin, T., Ngo, S. T., Steyn, F. J., Wallace, L., Williams, K. L., Neto, M., Cauchi, R. J., Blair, I. P., Kiernan, M. C., Drory, V., Povedano, M., de Carvalho, M., Pinto, S., Weber, M., Rouleau, G. A., Silani, V., Landers, J. E., Shaw, C. E., Andersen, P. M., McRae, A. F., van Es, M. A., Pasterkamp, R., Wray, N. R., McLaughlin, R. L., Hardiman, O., Kenna, K. P., Tsai, E., Runz, H., Al-Chalabi, A., van den Berg, L. H., Van Damme, P., Mill, J., Veldink, J. H., BIOS Consortium, Brain MEND Consortium 2022; 14 (633): eabj0264

  Abstract

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.

  View details for DOI 10.1126/scitranslmed.abj0264

  View details for Web of Science ID 000760127200002

  View details for PubMedID 35196023

  View details for PubMedCentralID PMC10040186

• Association of Essential Tremor With Novel Risk Loci A Genome-Wide Association Study and Meta-analysis JAMA NEUROLOGY Liao, C., Castonguay, C., Heilbron, K., Vuokila, V., Medeiros, M., Houle, G., Akcimen, F., Ross, J. P., Catoire, H., Diez-Fairen, M., Kang, J., Mueller, S. H., Girard, S. L., Hopfner, F., Lorenz, D., Clark, L. N., Soto-Beasley, A. I., Klebe, S., Hallett, M., Wszolek, Z. K., Pendziwiat, M., Lorenzo-Betancor, O., Seppi, K., Berg, D., Vilarino-Guell, C., Postuma, R. B., Bernard, G., Dupre, N., Jankovic, J., Testa, C. M., Ross, O. A., Arzberger, T., Chouinard, S., Louis, E. D., Mandich, P., Vitale, C., Barone, P., Garcia-Martin, E., Alonso-Navarro, H., Agundez, J. A. G., Jimenez-Jimenez, F., Pastor, P., Rajput, A., Deuschl, G., Kuhlenbaumer, G., Meijer, I. A., Dion, P. A., Rouleau, G. A. 2022; 79 (2): 185-193

  Abstract

  Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified.To identify common genetic factors associated with risk of ET.Case-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts. Multicenter samples collected from European populations were collected from January 2010 to September 2019 as part of an ongoing study. Included patients were clinically diagnosed with or reported having ET. Control individuals were not diagnosed with or reported to have ET. Of 485 250 individuals, data for 483 054 passed data quality control and were used.Genotypes of common variants associated with risk of ET.Of the 483 054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475 877 control individuals (253 785 [53.33%] female; mean [SD] age, 56.40 [17.6] years). Five independent genome-wide significant loci and were identified and were associated with approximately 18% of ET heritability. Functional analyses found significant enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways. Genetic correlation (r), which measures the degree of genetic overlap, revealed significant common variant overlap with Parkinson disease (r, 0.28; P = 2.38 × 10-8) and depression (r, 0.12; P = 9.78 × 10-4). A separate fine-mapping of transcriptome-wide association hits identified genes such as BACE2, LRRN2, DHRS13, and LINC00323 in disease-relevant brain regions, such as the cerebellum.The results of this genome-wide association study suggest that a portion of ET heritability can be explained by common genetic variation and can help identify new common genetic risk factors for ET.

  View details for DOI 10.1001/jamaneurol.2021.4781

  View details for Web of Science ID 000739991000003

  View details for PubMedID 34982113

  View details for PubMedCentralID PMC8728658

• 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

  Abstract

  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

• Occurrence of Amyotrophic Lateral Sclerosis in Type 1 Gaucher Disease NEUROLOGY-GENETICS Oliveira, L. M., Rastin, T., Nimmo, G. A. M., Ross, J. P., Dion, P. A., Zhang, M., Nevay, D., Arkadir, D., Gotkine, M., Barnett, C., Shoesmith, C. L., Zimran, A., Rogaeva, E. A., Zinman, L., Rouleau, G. A., Gan-Or, Z., Amato, D., Kalia, L. 2021; 7 (4): e600

  Abstract

  To report the association between type 1 Gaucher disease (GD1) and amyotrophic lateral sclerosis (ALS) in 3 unrelated families and to explore whether GBA variants influence the risk of ALS.We conducted retrospective chart reviews of patients with GD1 or their family members diagnosed with ALS. To further investigate whether there is an association between ALS and GD, we performed exploratory analyses for the presence of GBA variants in 3 ALS cohorts from Toronto (Canada), Montreal (Canada), and Project MinE (international), totaling 4,653 patients with ALS and 1,832 controls.We describe 2 patients with GD1 and 1 obligate GBA mutation carrier (mother of GD1 patient) with ALS. We identified 0 and 8 GBA carriers in the Toronto and Montreal cohorts, respectively. The frequencies of GBA variants in patients with ALS in the Montreal and Project MinE cohorts were similar to those of Project MinE controls or Genome Aggregation Database population controls.The occurrence of ALS in biallelic or monoallelic GBA mutation carriers described here, in addition to common pathogenic pathways shared by GD1 and ALS, suggests that GBA variants could influence ALS risk. However, analyses of GBA variants in ALS cohorts did not reveal a meaningful association. Examination of larger cohorts and neuropathologic studies will be required to elucidate whether patients with GD1 are indeed at increased risk for ALS.

  View details for DOI 10.1212/NXG.0000000000000600

  View details for Web of Science ID 000711761500002

  View details for PubMedID 34017912

  View details for PubMedCentralID PMC8130998

• Evidence for Non-Mendelian Inheritance in Spastic Paraplegia 7 MOVEMENT DISORDERS Estiar, M. A., Yu, E., Haj Salem, I., Ross, J. P., Mufti, K., Akcimen, F., Leveille, E., Spiegelman, D., Ruskey, J. A., Asayesh, F., Dagher, A., Yoon, G., Tarnopolsky, M., Boycott, K. M., Dupre, N., Dion, P. A., Suchowersky, O., Trempe, J., Rouleau, G. A., Gan-Or, Z. 2021; 36 (7): 1664-1675

  Abstract

  Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant hereditary spastic paraplegia (HSP).We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association of SPG7 and HSP.We analyzed 585 HSP patients from 372 families and 1175 controls, including 580 unrelated individuals. Whole-exome sequencing was performed on 400 HSP patients (291 index cases) and all 1175 controls.The frequency of heterozygous pathogenic/likely pathogenic SPG7 variants (4.8%) among unrelated HSP patients was higher than among unrelated controls (1.7%; OR 2.88, 95% CI 1.24-6.66, P = 0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index patients versus 0.85% in unrelated controls (OR 4.42, 95% CI 1.49-13.07, P = 0.005). Similar results were obtained after including only genetically-undiagnosed patients. We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, compared to zero in controls (OR 19.58, 95% CI 1.05-365.13, P = 0.0031), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2). Of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function.Our results provide evidence for complex inheritance in SPG7-associated HSP, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance. © 2021 International Parkinson and Movement Disorder Society.

  View details for DOI 10.1002/mds.28528

  View details for Web of Science ID 000618869400001

  View details for PubMedID 33598982

• Expanded CAG Repeats in <i>ATXN1</i>, <i>ATXN2</i>, <i>ATXN3</i>, and <i>HTT</i> in the 1000 Genomes Project MOVEMENT DISORDERS Akcimen, F., Ross, J. P., Liao, C., Spiegelman, D., Dion, P. A., Rouleau, G. A. 2021; 36 (2): 514-518

  Abstract

  Spinocerebellar ataxia types 1, 2, 3 and Huntington disease are neurodegenerative disorders caused by expanded CAG repeats.We performed an in-silico analysis of CAG repeats in ATXN1, ATXN2, ATXN3, and HTT using 30× whole-=genome sequencing data of 2504 samples from the 1000 Genomes Project.Seven HTT-positive, 3 ATXN2-positive, 1 ATXN3-positive, and 6 possibly ATXN1-positive samples were identified. No correlation was found between the repeat sizes of the different genes. The distribution of CAG alleles varied by ethnicity.Our results suggest that there may be asymptomatic small expanded repeats in almost 0.5% of these populations. © 2020 International Parkinson and Movement Disorder Society.

  View details for DOI 10.1002/mds.28341

  View details for Web of Science ID 000586997800001

  View details for PubMedID 33159825

• Assessing the <i>NOTCH2NLC</i> GGC expansion in European patients with essential tremor BRAIN Liao, C., Akcimen, F., Diez-Fairen, M., Houle, G., Ross, J. P., Schmilovich, Z., Spiegelman, D., Vuokila, V., Catoire, H., Meijer, I. A., Pastor, P., Rajput, A., Dion, P. A., Rouleau, G. A. 2020; 143: e89

  View details for DOI 10.1093/brain/awaa291

  View details for Web of Science ID 000607114000001

  View details for PubMedID 33146671

• Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes COMMUNICATIONS BIOLOGY Akcimen, F., Sarayloo, F., Liao, C., Ross, J. P., Oliveira, R., Dion, P. A., Rouleau, G. A. 2020; 3 (1): 373

  Abstract

  Restless legs syndrome (RLS) is a common neurological condition, with a prevalence of 5-15% in Central Europe and North America. Although genome-wide association studies (GWAS) have identified some common risk regions for RLS, the causal genes have yet to be fully elucidated. We conducted a transcriptome-wide association study involving 15,126 RLS cases and 95,725 controls, from the most recent meta-analysis of GWAS, and gene expression weights of GTEx v7 and the CMC dorsolateral prefrontal cortex tissue panels. We identified 13 associations (in 8 independent loci) at the transcriptome-wide significant level, of which 6 were not implicated in the previous GWAS: SKAP1, SLC36A1, CCDC57, FN3KRP, NCOA6/TRPC4AP. A fine-mapping approach prioritized CMTR1, RP1-153P14.5, PRPF6, and PPP3R1 - to our knowledge, the latter of which is the first RLS-associated gene directly implicated in dopaminergic pathways. Overall, our findings highlight the power of integrating gene expression data with GWAS to prioritize putative causal genes for functional follow-up studies.

  View details for DOI 10.1038/s42003-020-1105-z

  View details for Web of Science ID 000552089800006

  View details for PubMedID 32651461

  View details for PubMedCentralID PMC7351781

• 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

  Abstract

  "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

  Abstract

  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

• Genetic and epidemiological characterization of restless legs syndrome in Quebec SLEEP Akcimen, F., Ross, J. P., Sarayloo, F., Liao, C., De Barros Oliveira, R., Ruskey, J. A., Bourassa, C. V., Dion, P. A., Xiong, L., Gan-Or, Z., Rouleau, G. A. 2020; 43 (4)

  Abstract

  Currently, a total of 19 genetic loci are associated with the risk for developing RLS. This study aimed to assess these RLS predisposing genetic variants, as well as investigate the epidemiological profile and diagnostic features of individuals with RLS in the Québec population, using an interviewer-administered questionnaire. A total of 18 RLS-associated variants were genotyped in the Québec population-based CARTaGENE cohort. A case-control series consisting of 1,362 RLS cases and 1,379 age-matched unaffected controls was used to conduct a genetic and epidemiological association study that integrated the first four RLS diagnostic features of affected individuals, as well as additional RLS-related questions (e.g. frequency of the symptoms and number of total pregnancies in female). Five RLS-predisposing variants were significantly associated after Bonferroni correction and an additional five variants were nominally associated with RLS (p < 0.05). BTBD9 was the strongest genetic risk factor in our cohort (rs9296249, OR = 1.71, p = 9.57 × 10-10). The patient group that met all four essential diagnostic criteria of RLS provided the most significant genetic findings. These results suggest that employing the questionnaire which included standard diagnostic criteria of RLS could improve the accuracy of the survey-based studies.

  View details for DOI 10.1093/sleep/zsz265

  View details for Web of Science ID 000537432400014

  View details for PubMedID 31665514

• 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

  Abstract

  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

• Investigation of the <i>RFC1</i> Repeat Expansion in a Canadian and a Brazilian Ataxia Cohort: Identification of Novel Conformations FRONTIERS IN GENETICS Akcimen, F., Ross, J. P., Bourassa, C., Liao, C., Rochefort, D., Drumond Gama, M., Dicaire, M., Barsottini, O. G., Brais, B., Pedroso, J., Dion, P. A., Rouleau, G. A. 2019; 10: 1219

  Abstract

  A biallelic pentanucleotide expansion in the RFC1 gene has been reported to be a common cause of late-onset ataxia. In the general population, four different repeat conformations are observed: wild type sequence AAAAG (11 repeats) and longer expansions of either AAAAG, AAAGG or AAGGG sequences. However only the biallelic AAGGG expansions were reported to cause late-onset ataxia. In this study, we aimed to assess the prevalence and nature of RFC1 repeat expansions in three cohorts of adult-onset ataxia cases: Brazilian (n = 23) and Canadian (n = 26) cases that are negative for the presence of variants in other known ataxia-associated genes, as well as a cohort of randomly selected Canadian cases (n = 128) without regard to a genetic diagnosis. We identified the biallelic AAGGG expansion in only one Brazilian family which presented two affected siblings, and in one Canadian case. We also observed two new repeat conformations, AAGAG and AGAGG, which suggests the pentanucleotide expansion sequence has a dynamic nature. To assess the frequency of these new repeat conformations in the general population, we screened 163 healthy individuals and observed the AAGAG expansion to be more frequent in cases than in control individuals. While additional studies will be necessary to asses the pathogenic impact of biallelic genotypes that include the novel expanded conformations, their occurrence should nonetheless be examined in future studies.

  View details for DOI 10.3389/fgene.2019.01219

  View details for Web of Science ID 000501797700001

  View details for PubMedID 31824583

  View details for PubMedCentralID PMC6884024

• Mineral absorption is an enriched pathway in a brain region of restless legs syndrome patients with reduced <i>MEIS1</i> expression PLOS ONE Sarayloo, F., Dionne-Laporte, A., Catoire, H., Rochefort, D., Houle, G., Ross, J. P., Akcimen, F., Oliveira, R., Turecki, G., Dion, P. A., Rouleau, G. A. 2019; 14 (11): e0225186

  Abstract

  Restless legs syndrome is a common complex disorder with different genetic and environmental risk factors. Here we used human cell lines to conduct an RNA-Seq study and observed how the gene showing the most significant association with RLS, MEIS1, acts as a regulator of the expression of many other genes. Some of the genes affected by its expression level are linked to pathways previously reported to be associated with RLS. We found that in cells where MEIS1 expression was either increased or prevented, mineral absorption is the principal dysregulated pathway. The mineral absorption pathway genes, HMOX1 and VDR are involved in iron metabolism and response to vitamin D, respectively. This shows a strong functional link to the known RLS pathways. We observed the same enrichment of the mineral absorption pathway in postmortem brain tissues of RLS patients showing a reduced expression of MEIS1. The expression of genes encoding metallothioneins (MTs) was observed to be dysregulated across the RNA-Seq datasets generated from both human cells and tissues. MTs are highly relevant to RLS as they bind intracellular metals, protect against oxidative stress and interact with ferritins which manage iron level in the central nervous system. Overall, our study suggests that in a subset of RLS patients, the contribution of MEIS1 appears to be associated to its downstream regulation of genes that are more directly involved in pathways that are relevant to RLS. While MTs have been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson's diseases, this is a first report to propose that they have a role in RLS.

  View details for DOI 10.1371/journal.pone.0225186

  View details for Web of Science ID 000532764500065

  View details for PubMedID 31725784

  View details for PubMedCentralID PMC6855629

• Mutations in <i>ATP13A2</i> (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expansion HUMAN GENOMICS Spataro, R., Kousi, M., Farhan, S. M. K., Willer, J. R., Ross, J. P., Dion, P. A., Rouleau, G. A., Daly, M. J., Neale, B. M., La Bella, V., Katsanis, N. 2019; 13: 19

  Abstract

  Amyotrophic lateral sclerosis [1] is a genetically heterogeneous neurodegenerative disorder, characterized by late-onset degeneration of motor neurons leading to progressive limb and bulbar weakness, as well as of the respiratory muscles, which is the primary cause of disease fatality. To date, over 25 genes have been implicated as causative in ALS with C9orf72, SOD1, FUS, and TARDBP accounting for the majority of genetically positive cases.We identified two patients of Italian and French ancestry with a clinical diagnosis of juvenile-onset ALS who were mutation-negative in any of the known ALS causative genes. Starting with the index case, a consanguineous family of Italian origin, we performed whole-exome sequencing and identified candidate pathogenic mutations in 35 genes, 27 of which were homozygous. We next parsed all candidates against a cohort of 3641 ALS cases; only ATP13A2 was found to harbor recessive changes, in a patient with juvenile-onset ALS, similar to the index case. In vivo complementation of ATP13A2 using a zebrafish surrogate model that focused on the assessment of motor neuron morphology and cerebellar integrity confirmed the role of this gene in central and peripheral nervous system maintenance and corroborated the damaging direction of effect of the change detected in the index case of this study.We here expand the phenotypic spectrum associated with genetic variants in ATP13A2 that previously comprised Kufor-Rakeb syndrome, spastic paraplegia 78, and neuronal ceroid lipofuscinosis type 12 (CLN12), to also include juvenile-onset ALS, as supported by both genetic and functional data. Our findings highlight the importance of establishing a complete genetic profile towards obtaining an accurate clinical diagnosis.

  View details for DOI 10.1186/s40246-019-0203-9

  View details for Web of Science ID 000465014400001

  View details for PubMedID 30992063

  View details for PubMedCentralID PMC6469102

• Somatic expansion of the C9orf72 hexanucleotide repeat does not occur in ALS spinal cord tissues NEUROLOGY-GENETICS Ross, J. P., Leblond, C. S., Catoire, H., Volkening, K., Strong, M., Zinman, L., Robertson, J., Dion, P. A., Rouleau, G. A. 2019; 5 (2): e317

  Abstract

  To test for somatic C9orf72 hexanucleotide repeat expansion (HRE) and hexanucleotide repeat length instability in the spinal cord of amyotrophic lateral sclerosis (ALS) cases.Whole and partial spinal cords of 19 ALS cases were dissected into transversal sections (5 mm thick). The presence of C9orf72 HRE was tested in each independent section using RepeatPrimed PCR and amplicon-size genotyping. Index measures for the testing of mosaicism were obtained through serial dilutions of genomic DNA from an individual carrying a germline C9orf72 HRE in the genomic DNA of an individual without a C9orf72 HRE.None of the sections examined supported the presence of a subpopulation of cells with a C9orf72 HRE. Moreover, the C9orf72 hexanucleotide repeat lengths measured were identical across all the spinal cord sections of each individual patient.We did not observe somatic instability of the C9orf72 HRE in disease relevant tissues of ALS cases.

  View details for DOI 10.1212/NXG.0000000000000317

  View details for Web of Science ID 000481665200007

  View details for PubMedID 31041398

  View details for PubMedCentralID PMC6454309

• Full Sequencing and Haplotype Analysis of <i>MAPT</i> in Parkinson's Disease and Rapid Eye Movement Sleep Behavior Disorder MOVEMENT DISORDERS Li, J., Ruskey, J. A., Arnulf, I., Dauvilliers, Y., Hu, M. T. M., Hoegl, B., Leblond, C. S., Zhou, S., Ambalavanan, A., Ross, J. P., Bourassa, C. V., Spiegelman, D., Laurent, S. B., Stefani, A., Charley Monaca, C., Cochen De Cock, V., Boivin, M., Ferini-Strambi, L., Plazzi, G., Antelmi, E., Young, P., Heidbreder, A., Labbe, C., Ferman, T. J., Dion, P. A., Fan, D., Desautels, A., Gagnon, J., Dupre, N., Fon, E. A., Montplaisir, J. Y., Boeve, B. F., Postuma, R. B., Rouleau, G. A., Ross, O. A., Gan-Or, Z. 2018; 33 (6): 1016-1020

  Abstract

  MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear.To study the role of MAPT variants in rapid eye movement sleep behavior disorder.Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT-associated variants and the entire coding sequence of MAPT were analyzed. Age-, sex-, and ethnicity-adjusted analyses were performed to examine the association between MAPT, PD, and rapid eye movement sleep behavior disorder.MAPT-H2 variants were associated with PD (odds ratios: 0.62-0.65; P = 0.010-0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12-2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48-0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder.Our results confirm the protective effect of the MAPT-H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus. © 2018 International Parkinson and Movement Disorder Society.

  View details for DOI 10.1002/mds.27385

  View details for Web of Science ID 000439829100020

  View details for PubMedID 29756641

• Association study of essential tremor genetic loci in Parkinson's disease NEUROBIOLOGY OF AGING Ross, J. P., Mohtashami, S., Leveille, E., Johnson, A. M., Xiong, L., Dion, P. A., Fon, E., Dauvilliers, Y., Dupre, N., Rouleau, G. A., Gan-Or, Z. 2018; 66: 178.e13-178.e15

  Abstract

  A recent genome-wide association study identified variants associated with essential tremor (ET). The present study aimed to examine potential genetic overlap between ET and Parkinson's disease (PD). The top 22 variants identified by the ET genome-wide association study and 4 additional variants from previous studies were genotyped in a cohort of French and French-Canadian PD patients (n = 717) and controls (n = 595). Logistic regression analysis, adjusted for age and sex, was used to test for association between genotype and PD. None of the variants tested in the present study was significantly associated with PD. Our results do not support a role of ET-associated genetic variants in PD.

  View details for DOI 10.1016/j.neurobiolaging.2018.01.001

  View details for Web of Science ID 000431006300023

  View details for PubMedID 29398123

• Genome-wide association analysis identifies new candidate risk loci for familial intracranial aneurysm in the French-Canadian population SCIENTIFIC REPORTS Zhou, S., Gan-Or, Z., Ambalavanan, A., Lai, D., Xie, P., Bourassa, C. V., Strong, S., Ross, J. P., Dionne-Laporte, A., Spiegelman, D., Dupre, N., Foroud, T. M., Xiong, L., Dion, P. A., Rouleau, G. A. 2018; 8: 4356

  Abstract

  Intracranial Aneurysm (IA) is a common disease with a worldwide prevalence of 1-3%. In the French-Canadian (FC) population, where there is an important founder effect, the incidence of IA is higher and is frequently seen in families. In this study, we genotyped a cohort of 257 mostly familial FC IA patients and 1,992 FC controls using the Illumina NeuroX SNP-chip. The most strongly associated loci were tested in 34 Inuit IA families and in 32 FC IA patients and 106 FC controls that had been exome sequenced (WES). After imputation, one locus at 3p14.2 (FHIT, rs1554600, p = 4.66 × 10-9) reached a genome-wide significant level of association and a subsequent validation in Nunavik Inuit cohort further confirmed the significance of the FHIT variant association (rs780365, FBAT-O, p = 0.002839). Additionally, among the other promising loci (p < 5 × 10-6), the one at 3q13.2 (rs78125721, p = 4.77 × 10-7), which encompasses CCDC80, also showed an increased mutation burden in the WES data (CCDC80, SKAT-O, p = 0.0005). In this study, we identified two new potential IA loci in the FC population: FHIT, which is significantly associated with hypertensive IA, and CCDC80, which has potential genetic and functional relevance to IA pathogenesis, providing evidence on the additional risk loci for familial IA. We also replicated the previous IA GWAS risk locus 18q11.2, and suggested a potential locus at 8p23.1 that warrants further study.

  View details for DOI 10.1038/s41598-018-21603-7

  View details for Web of Science ID 000427116700008

  View details for PubMedID 29531279

  View details for PubMedCentralID PMC5847615

• Genetic modifiers of multiple sclerosis progression, severity and onset CLINICAL IMMUNOLOGY Sadovnick, A., Traboulsee, A. L., Zhao, Y., Bernales, C. Q., Encarnacion, M., Ross, J. P., Yee, I. M., Criscuoli, M. G., Vilarino-Guell, C. 2017; 180: 100-105

  Abstract

  The genetic contribution to clinical outcomes for multiple sclerosis (MS) has yet to be defined. We performed exome sequencing analysis in 100 MS patients presenting opposite extremes of clinical phenotype (discovery cohort), and genotyped variants of interest in 2016 MS patients (replication cohort). Linear and logistic regression analyses were used to identify significant associations with disease course, severity and onset. Our analysis of the discovery cohort nominated 38 variants in 21 genes. Replication analysis identified PSMG4 p.W99R and NLRP5 p.M459I to be associated with disease severity (p=0.002 and 0.008). CACNA1H p.R1871Q was found associated with patients presenting relapsing remitting MS at clinical onset (p=0.028) whereas NLRP5 p.M459I and EIF2AK1 p.K558R were associated with primary progressive disease (p=0.031 and 0.023). In addition, PSMG4 p.W99R and NLRP5 p.R761L were found to correlate with an earlier age at MS clinical onset, and MC1R p.R160W with delayed onset of clinical symptoms (p=0.010-0.041).

  View details for DOI 10.1016/j.clim.2017.05.009

  View details for Web of Science ID 000403998600015

  View details for PubMedID 28501589

• <i>RIC3</i> variants are not associated with Parkinson's disease in French-Canadians and French NEUROBIOLOGY OF AGING Ross, J. P., Dupre, N., Dauvilliers, Y., Strong, S., Dionne-Laporte, A., Dion, P. A., Rouleau, G. A., Gan-Or, Z. 2017; 53: 194.e9-194.e11

  Abstract

  Variants in the RIC3 gene have recently been suggested as a novel cause of Parkinson's disease (PD). Herein, the entire RIC3 gene was sequenced in a French-Canadian and French sample series of 535 PD patients and 527 unaffected controls. The effect of single variants and the combined effect of variants were calculated. Sequence Kernel association tests (SKAT, SKAT-O) were done on the entire gene level, and on the different domains and exons of RIC3. A total of 28 common and rare variants were identified in patients and controls. No significant association was found between any variant and haplotype in RIC3 and PD, and there was no over-representation of RIC3 variants at the entire gene, domain, or exon levels in patients versus controls. Our results do not support a role for RIC3 mutations as a common cause of PD in the French-Canadian and French populations.

  View details for DOI 10.1016/j.neurobiolaging.2017.01.005

  View details for Web of Science ID 000399501300028

  View details for PubMedID 28153381

• Case-Control Studies Are Not Familial Studies NEURON Wang, Z., Sadovnick, A., Traboulsee, A. L., Ross, J. P., Bernales, C. Q., Encarnacion, M., Yee, I. M., de Lemos, M., Greenwood, T., Lee, J. D., Wright, G., Ross, C. J., Zhang, S., Song, W., Vilarino-Guell, C. 2016; 92 (2): 339-341

  Abstract

  Identifying rare genetic variants that drive the onset of disease is challenging, even before considering the additional genetic and environmental influences that likely exist in complex diseases. We recently published a study proposing a rare variant in the NR1H3 gene (p.R415Q, rs61731956) as responsible for the onset of multiple sclerosis (MS) in two multi-incident families (Wang et al., 2016). This publication has generated much discussion, and fortunately the possibility to validate a finding or prove it spurious can occur rapidly in genetic studies. All novel discoveries must be replicated, and best efforts should be made to ensure that these replications use the appropriate samples and approach, and provide the correct interpretation of the results. This Matters Arising Response paper addresses the Minikel and MacArthur (2016) and The International Multiple Sclerosis Genetics Consortium (2016) Matters Arising papers, published concurrently in Neuron.

  View details for DOI 10.1016/j.neuron.2016.09.053

  View details for Web of Science ID 000386762000017

  View details for PubMedID 27764669

• GBA P.T369M SUBSTITUTION IN PARKINSON DISEASE: POLYMORPHISM OR ASSOCIATION? A META-ANALYSIS NEUROLOGY-GENETICS Mallett, V., Ross, J. P., Alcalay, R. N., Ambalavanan, A., Sidransky, E., Dion, P. A., Rouleau, G. A., Gan-Or, Z. 2016; 2 (5): e104

  Abstract

  The lysosomal enzyme glucocerebrosidase (GCase), encoded by GBA, has an important role in Parkinson disease (PD). GBA mutation carriers have an increased risk for PD, earlier age at onset, faster progression, and various nonmotor symptoms including cognitive decline, REM sleep behavior disorder, hyposmia, and autonomic dysfunction.(1) Furthermore, GCase enzymatic activity is reduced in the peripheral blood(2) and brain(3) of noncarrier, sporadic PD patients. Biallelic GBA mutations, which have been classified as "severe" or "mild," may cause Gaucher disease (GD), a lysosomal storage disorder. Mild mutations may lead to GD type 1, and 2 severe mutations result in neuronopathic GD (type 2 and type 3).(4) There are 2 GBA variants, p.E326K and p.T369M, which do not cause GD in homozygous carriers, but may modify GCase activity and GD phenotype. It is now clear that p.E326K is a risk factor for PD,(5) but whether p.T369M is associated with PD is still controversial. In some studies, the p.T369M substitution was associated with PD,(6) while in others it had similar or increased frequency in controls. Of interest, it was recently demonstrated that the GBA p.T369M substitution was associated with reduced enzymatic activity in patients with PD and controls compared with that in noncarriers (7.64 vs 11.93 μmol/L/h, p < 0.001).(2) Of interest, it was even lower than the average enzymatic activity of the p.E326K substitution, which was 9.81 μmol/L/h. Because clinical trials on GBA-associated PD are ongoing, and because treatment specifically targeting GBA is likely to be available in the future, it is important to determine whether the GBA p.T369M substitution is associated with PD.

  View details for DOI 10.1212/NXG.0000000000000104

  View details for Web of Science ID 000445340800011

  View details for PubMedID 27648471

  View details for PubMedCentralID PMC5017539

• Analysis of <i>DNAJC13</i> mutations in French-Canadian/French cohort of Parkinson's disease NEUROBIOLOGY OF AGING Ross, J. P., Dupre, N., Dauvilliers, Y., Strong, S., Ambalavanan, A., Spiegelman, D., Dionne-Laporte, A., Pourcher, E., Langlois, M., Boivin, M., Leblond, C. S., Dion, P. A., Rouleau, G. A., Gan-Or, Z. 2016; 45: 212.e13-212.e17

  Abstract

  DNAJC13 mutations have been suggested to cause Parkinson's disease (PD), yet subsequent studies reported conflicting results on this association. In the present study, we sequenced the coding region of DNAJC13 in a French-Canadian/French cohort of 528 PD patients and 692 controls. A total of 62 (11.7%) carriers of rare DNAJC13 variants were identified among the PD patients compared with 82 (11.8%) among controls (p = 1.0). Two variants that were previously suggested to be associated with PD, p.R1516H and p.L2170W, were identified with similar directions of association as previously reported. The p.R1516H was found in 2 (0.4%) patients versus 6 (0.9%, nonsignificant) controls and the p.L2170W variant was found in 9 (1.7%) patients and 5 (0.7%, nonsignificant) controls. Meta-analysis with previous reports resulted in odds ratios of 0.32 (95% confidence interval = 0.15-0.68, p = 0.0037) and 2.68 (95% confidence interval = 1.32-5.42, p = 0.007), respectively. Our results provide some support for the possibility that specific DNAJC13 variants may play a minor role in PD susceptibility, although studies in additional populations are necessary.

  View details for DOI 10.1016/j.neurobiolaging.2016.04.023

  View details for Web of Science ID 000381092900023

  View details for PubMedID 27236598

• Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients G3-GENES GENOMES GENETICS Sadovnick, A., Traboulsee, A. L., Bernales, C. Q., Ross, J. P., Forwell, A. L., Yee, I. M., Guillot-Noel, L., Fontaine, B., Cournu-Rebeix, I., Alcina, A., Fedetz, M., Izquierdo, G., Matesanz, F., Hilven, K., Dubois, B., Goris, A., Astobiza, I., Alloza, I., Antigueedad, A., Vandenbroeck, K., Akkad, D. A., Aktas, O., Blaschke, P., Buttmann, M., Chan, A., Epplen, J. T., Gerdes, L., Kroner, A., Kubisch, C., Kuempfel, T., Lohse, P., Rieckmann, P., Zettl, U. K., Zipp, F., Bertram, L., Lill, C. M., Fernandez, O., Urbaneja, P., Leyva, L., Carlos Alvarez-Cermeno, J., Arroyo, R., Garagorri, A. M., Garcia-Martinez, A., Villar, L. M., Urcelay, E., Malhotra, S., Montalban, X., Comabella, M., Berger, T., Fazekas, F., Reindl, M., Schmied, M. C., Zimprich, A., Vilarino-Guell, C. 2016; 6 (7): 2073-2079

  Abstract

  Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93-1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.

  View details for DOI 10.1534/g3.116.030841

  View details for Web of Science ID 000379590200027

  View details for PubMedID 27194806

  View details for PubMedCentralID PMC4938660

• Nuclear Receptor NR1H3 in Familial Multiple Sclerosis NEURON Wang, Z., Sadovnick, A., Traboulsee, A. L., Ross, J. P., Bernales, C. Q., Encarnacion, M., Yee, I. M., de Lemos, M., Greenwood, T., Lee, J. D., Wright, G., Ross, C. J., Zhang, S., Song, W., Vilarino-Guell, C. 2016; 90 (5): 948-954

  Abstract

  Multiple sclerosis (MS) is an inflammatory disease characterized by myelin loss and neuronal dysfunction. Despite the aggregation observed in some families, pathogenic mutations have remained elusive. In this study, we describe the identification of NR1H3 p.Arg415Gln in seven MS patients from two multi-incident families presenting severe and progressive disease, with an average age at onset of 34 years. Additionally, association analysis of common variants in NR1H3 identified rs2279238 conferring a 1.35-fold increased risk of developing progressive MS. The p.Arg415Gln position is highly conserved in orthologs and paralogs, and disrupts NR1H3 heterodimerization and transcriptional activation of target genes. Protein expression analysis revealed that mutant NR1H3 (LXRA) alters gene expression profiles, suggesting a disruption in transcriptional regulation as one of the mechanisms underlying MS pathogenesis. Our study indicates that pharmacological activation of LXRA or its targets may lead to effective treatments for the highly debilitating and currently untreatable progressive phase of MS.

  View details for DOI 10.1016/j.neuron.2016.04.039

  View details for Web of Science ID 000378523900009

  View details for PubMedID 27253448

  View details for PubMedCentralID PMC5092154

• Analysis of CH25H in multiple sclerosis and neuromyelitis optica JOURNAL OF NEUROIMMUNOLOGY Forwell, A. L., Bernales, C. Q., Ross, J. P., Yee, I. M., Encarnacion, M., Lee, J. D., Sadovnick, A., Traboulsee, A. L., Vilarino-Gueell, C. 2016; 291: 70-72

  Abstract

  Oxysterols produced by CH25H during cholesterol metabolism have been shown to play an important role in the immune response. In this study we report the genetic characterization of CH25H in patients diagnosed with multiples sclerosis (MS) or neuromyelitis optica (NMO), for the identification of genetic variants affecting disease susceptibility and course. Exome analysis in 212 MS and 14 NMO patients identified a rare CH25H p.Q17H mutation in two NMO patients of Asian ancestry. In addition, association analysis of common CH25H variants identified a nominally significant association with MS patients presenting a clinical course consistent with primary progressive disease.

  View details for DOI 10.1016/j.jneuroim.2015.12.014

  View details for Web of Science ID 000370906900010

  View details for PubMedID 26857497

  View details for PubMedCentralID PMC5092160