DOCSLIB.ORG

Evidence for Polygenic and Oligogenic Basis of Australian Sporadic

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Evidence for Polygenic and Oligogenic Basis of Australian Sporadic Neurogenetics J Med Genet: first published as 10.1136/jmedgenet-2020-106866 on 14 May 2020. Downloaded from Original research Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis Emily P McCann ,1 Lyndal Henden ,1 Jennifer A Fifita ,1 Katharine Y Zhang,1 Natalie Grima ,1 Denis C Bauer ,2 Sandrine Chan Moi Fat ,1 Natalie A Twine ,1,2 Roger Pamphlett ,3,4,5 Matthew C Kiernan,4,6 Dominic B Rowe ,1,7 Kelly L Williams ,1 Ian P Blair 1 ► Additional material is ABSTRact present with limb onset and 25% with bulbar onset, published online only. To view, Background Amyotrophic lateral sclerosis (ALS) is a while rare cases show truncal onset.3 The median please visit the journal online fatal neurodegenerative disease with phenotypic and disease course is 3 years,2 however survival can be (http:// dx. doi. org/ 10. 1136/ 2 4 jmedgenet- 2020- 106866). genetic heterogeneity. Approximately 10% of cases are as short as 12 months and may exceed 20 years. familial, while remaining cases are classified as sporadic. Around 10%–15% of ALS cases are diagnosed with For numbered affiliations see To date, >30 genes and several hundred genetic variants comorbid frontotemporal dementia (FTD), with up end of article. have been implicated in ALS. to 50% developing some cognitive impairment.5 Methods Seven hundred and fifty- seven sporadic Approximately 10% of ALS cases have a family Correspondence to Dr Ian P Blair, Biomedical ALS cases were recruited from Australian neurology history of disease (familial ALS (FALS)) and two- Sciences, Macquarie University clinics. Detailed clinical data and whole genome thirds of these cases carry a reported ALS gene Faculty of Medicine and Health sequencing (WGS) data were available from 567 and mutation.6 7 The remaining 90% of cases have Sciences, Sydney, NSW 2109, 616 cases, respectively, of which 426 cases had both no apparent family history and are classified as Australia; ian. blair@ mq. edu. au datasets available. As part of a comprehensive genetic sporadic ALS (SALS). EPM, LH and JAF are joint first analysis, 853 genetic variants previously reported as Extensive genetic heterogeneity is apparent authors. ALS- linked mutations or disease- associated alleles among ALS cases. To date, at least 31 genes have KLW and IPB are joint senior were interrogated in sporadic ALS WGS data. Statistical been linked or associated with ALS. Heritability authors. analyses were performed to identify correlation studies suggest that 40%–60% of SALS risk may be 8–10 Received 20 January 2020 between clinical variables, and between phenotype explained by genetic factors. A polygenic basis Revised 2 March 2020 and the number of ALS- implicated variants carried by to SALS has been implicated by the co- occurrence Accepted 22 March 2020 an individual. Relatedness between individuals carrying of two or more ALS gene variants in a single indi- Published Online First 14 May identical variants was assessed using identity- by- descent vidual.11–14 These variants likely interact with envi- 2020 analysis. ronmental factors to trigger the development of http://jmg.bmj.com/ Results Forty- three ALS- implicated variants from 18 ALS.15 Alternatively, this may indicate an oligogenic genes, including C9orf72, ATXN2, TARDBP, SOD1, disease model,11 where an ALS mutation of large SQSTM1 and SETX, were identified in Australian effect, such as SOD1 or C9orf72, is inherited with sporadic ALS cases. One- third of cases carried at least another ALS gene variant which may also contribute one variant and 6.82% carried two or more variants, to phenotype. Furthermore, a multistep hypoth- implicating a potential oligogenic or polygenic basis of esis has recently been postulated to explain the ALS. Relatedness was detected between two sporadic 16 late and apparently sporadic onset of ALS. This on September 26, 2021 by guest. Protected copyright. ALS cases carrying a SOD1 p.I114T mutation, and among hypothesis postulates that six ‘steps’ are required three cases carrying a SQSTM1 p.K238E mutation. to trigger ALS onset, where such steps may include Oligogenic/polygenic sporadic ALS cases showed earlier genetic predisposition, environmental exposures or age of onset than those with no reported variant. 16 Conclusion We confirm phenotypic associations among other unknown molecular alterations. Within this ALS cases, and highlight the contribution of genetic hypothesis, known genetic mutations may account variation to all forms of ALS. for multiple steps, to a degree reflective of their penetrance.17 Previously, our laboratory described the genetic and phenotypic heterogeneity of Australian familial 7 INTRODUCTION ALS. Here, we report the extent of phenotypic Amyotrophic lateral sclerosis (ALS) is a late- onset and genetic variation among Australian SALS cases. fatal neurodegenerative disease characterised by To interrogate the genetic architecture of Austra- lian SALS, we first compiled a list of 31 genes, and © Author(s) (or their the degeneration of both upper and lower motor 1 employer(s)) 2021. No neurons. Patients develop muscle weakness, >850 genetic variants previously reported as: 1) commercial re- use. See rights wasting, spasticity and eventual paralysis. ALS ALS- linked mutations (typically identified from and permissions. Published displays significant phenotypic heterogeneity, even family based studies); 2) functional risk alleles (vari- by BMJ. among cases with identical causal gene mutations. ants whose functions are thought to increase disease To cite: McCann EP, Disease onset can occur anywhere from the second susceptibility) or 3) otherwise associated variants Henden L, Fifita JA, et al. to ninth decade of life but most frequently between (including variants that may be in linkage disequi- J Med Genet 2021;58:87–95. 50 and 60 years of age.2 Around 70% of cases librium with unknown functional risk alleles). McCann EP, et al. J Med Genet 2021;58:87–95. doi:10.1136/jmedgenet-2020-106866 87 Neurogenetics J Med Genet: first published as 10.1136/jmedgenet-2020-106866 on 14 May 2020. Downloaded from Among a large Australian SALS cohort, 35.39% of cases carried with the addition of the recently reported ALS genes TIA123 and a variant previously reported in ALS, implicating 18 genes as KIF5A,24 as well as the GPX3- TNIP1 locus.25 A comprehensive contributing to disease in this population. Polygenic inheritance literature search was conducted in order to compile an exhaus- was implicated in 6.82% of SALS cases who harboured more tive reference list of 853 genetic variants previously implicated than one ALS-implicated variant. We also showed that the clin- in ALS (online supplementary file 2), including ALS-linked ical heterogeneity of Australian SALS is similar to that observed mutations, functional risk alleles and disease-associated variants. in cohorts from other populations. This involved performing a PubMed (https://www.ncbi. nlm. nih. gov/ pubmed/) search for each ALS gene name and ‘amyo- METHODS trophic lateral sclerosis’, with subsequent manual evaluation of all resulting publications. The ALSOD database (http:// alsod. iop. Subjects 26 A total of 757 SALS cases were recruited from the Macquarie kcl.ac. uk/ home. aspx; last updated 8 September 2015) was also University Neurodegenerative Disease Biobank, Australian consulted. MND DNA Bank (Royal Prince Alfred Hospital) and Brain and Genetic variants were included in this reference list (online Mind Centre (University of Sydney). All participants provided supplementary file 2) if they were predicted to alter the amino informed written consent as approved by the human research acid sequence of a protein (ie, non- synonymous/missense, frame- ethics committees of Macquarie University, Sydney South West shift and non- frameshift insertions/deletions, splicing variants) Area Health District or The University of Sydney. All participants and were named in the main text of the publication (ie, vari- were of Caucasian descent (as established according to online ants included in an aggregate of variants used for burden testing supplementary file 1), each was clinically diagnosed with definite were not added to the list). Details of genomic location (hg19), or probable ALS according to El Escorial criteria,18 and had no the transcript accession number and cDNA and protein changes known relatives affected by ALS and/or FTD. Of these 757 cases, were recorded for each variant. For variants where these details detailed clinical data were available for 567 individuals, and were not reported in the original publication(s), they were deter- 616 cases underwent whole genome sequencing (WGS), with a mined using the University of California Santa Cruz Variant total of 426 having both detailed clinical and WGS data avail- Annotation Integrator (http:// genome. ucsc.edu/ cgi- bin/ hgVai) able. Genomic DNA was extracted from peripheral blood using and the associated Human Genome Variation Society variant standard protocols. Fifteen of these SALS cases were previously nomenclature track. Ancillary details pertaining to the ancestry reported to carry an expansion in C9orf72.7 14 and ALS inheritance mode for cases carrying each variant were also recorded, as was the presence of each variant in unaffected and unrelated control individuals, where available in the original Statistical analysis of clinical variables publication(s). Clinical records were examined for four phenotypic features: sex, age at disease onset, site of onset (bulbar or spinal) and duration of disease from onset (until death or last known date of Identifying ALS-implicated variants in SALS cases survival). All statistical analyses were performed in R (V.3.5.1). WGS data from 616 SALS cases were parsed for 31 ALS genes Statistical analyses were performed in a pairwise fashion (online supplementary table 1) using custom UNIX scripts. between all four clinical variables to identify significant associa- Filtering using R was subsequently used to identify the previ- 2 tions. A χ analysis was performed between sex and site of onset, ously reported ALS-implicated variants (online supplementary http://jmg.bmj.com/ while Welch’s t- tests were performed between age of onset and file 2) present within this dataset.
Load more

Recommended publications
  • Genome-Wide Analyses Identify KIF5A As a Novel ALS Gene
    This is a repository copy of Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/129590/ Version: Accepted Version Article: Nicolas, A, Kenna, KP, Renton, AE et al. (210 more authors) (2018) Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron, 97 (6). 1268-1283.e6. https://doi.org/10.1016/j.neuron.2018.02.027 Reuse This article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) licence. This licence only allows you to download this work and share it with others as long as you credit the authors, but you can’t change the article in any way or use it commercially. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Genome-wide Analyses Identify KIF5A as a Novel ALS Gene Aude Nicolas1,2, Kevin P. Kenna2,3, Alan E. Renton2,4,5, Nicola Ticozzi2,6,7, Faraz Faghri2,8,9, Ruth Chia1,2, Janice A. Dominov10, Brendan J. Kenna3, Mike A. Nalls8,11, Pamela Keagle3, Alberto M. Rivera1, Wouter van Rheenen12, Natalie A. Murphy1, Joke J.F.A. van Vugt13, Joshua T. Geiger14, Rick A. Van der Spek13, Hannah A. Pliner1, Shankaracharya3, Bradley N.
    [Show full text]
  • Analysis of Shared Common Genetic Risk Between Amyotrophic Lateral Sclerosis and Epilepsy
    Neurobiology of Aging xxx (2020) 1.e1e1.e5 Contents lists available at ScienceDirect Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging Negative results Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy Dick Schijvena,b,c, Remi Stevelinkd, Mark McCormackd,e, Wouter van Rheenena, Jurjen J. Luykxb, Bobby P.C. Koelemand, Jan H. Veldinka,*, on behalf of the Project MinE ALS GWAS Consortium International League Against Epilepsy Consortium on Complex Epilepsies a Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands b Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands c Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands d Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands e Department of Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland article info abstract Article history: Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the Received 23 September 2019 latest and largest genome-wide studies in amyotrophic lateral sclerosis (n ¼ 36,052) and epilepsy (n ¼ Received in revised form 31 January 2020 38,349) to determine genetic overlap between these conditions. First, we showed no significant ge- Accepted 10 April 2020 netic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases.
    [Show full text]
  • Value of Systematic Genetic Screening of Patients with Amyotrophic Lateral
    Neurodegeneration J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-325014 on 14 February 2021. Downloaded from Original research Value of systematic genetic screening of patients with amyotrophic lateral sclerosis Stephanie R Shepheard ,1 Matthew D Parker,1 Johnathan Cooper- Knock ,1 Nick S Verber,1 Lee Tuddenham,1 Paul Heath,1 Nick Beauchamp,2 Elsie Place,2 Elizabeth S A Sollars,2 Martin R Turner ,3 Andrea Malaspina,4 Pietro Fratta,5,6 Channa Hewamadduma,7 Thomas M Jenkins ,1 Christopher J McDermott ,1 Dennis Wang,8 Janine Kirby,1 Pamela J Shaw ,1,7 on behalf of the Project MINE Consortium ► Additional material is ABSTRACT mild cognitive impairment, with approximately published online only. To view, Objective The clinical utility of routine genetic 5% progressing to clinically recognised fronto- please visit the journal online 1 (http:// dx. doi. org/ 10. 1136/ sequencing in amyotrophic lateral sclerosis (ALS) is temporal dementia (FTD). While the majority of jnnp- 2020- 325014). uncertain. Our aim was to determine whether routine ALS cases are considered sporadic (sALS), 5%–10% targeted sequencing of 44 ALS- relevant genes would have been shown to be familial, usually with auto- For numbered affiliations see have a significant impact on disease subclassification somal dominant inheritance, and the genetic cause end of article. and clinical care. of approximately 60%–70% of familial ALS (fALS) 2 Methods We performed targeted sequencing of a 44- cases has now been identified. The most common Correspondence to Professor Pamela J Shaw, gene panel in a prospective case series of 100 patients genetic cause of ALS is due to expansion of a Sheffield Institute for with ALS recruited consecutively from the Sheffield GGGGCC (G4C2) hexanucleotide repeat in the Translational Neuroscience, The Motor Neuron Disorders Clinic, UK.
    [Show full text]
  • Genetics and Genomics
    31st International Symposium on ALS/MND Theme 02 – Genetics and Genomics GEN-01: An Interval Look at Early outcomes of strength (ATLIS), bulbar function (quantitative speech analysis and IOPI), and disease Markers of Disease in Familial ALS progression (change in ALSFRS-R total score over time). Isabel Anez-Brunzual1, Austin Lewis, Katherine Burke1, Multiple measures of strength (ATLIS, HHD) and Diane Lucente1, Jennifer Jockel-Balsarotti2, Margaret cognition (NIH examiner, ALS-CBS) will be evaluated in all participants over time. Clapp2, Amber Malcolm2, Taylor Stirrat1, Stephanie Berry1, Tania Gendron3, Mercedes Prudencio3, Kathryn Results to date: Connaghan4, James Chan5, Jordan Green4, Leonard Petrucelli3, James Berry1, Timothy Miller2, Dr Katharine Interval analysis will be shown for 86 participants Nicholson1 enrolled in the DIALS Network. Forty-one of 86 1Massachusetts General Hospital, Boston, United States, participants are positive for an ALS causative mutation 2Washington University, Saint Louis, United States, 3Mayo (33 C9orf72, 5 SOD1, 1 TARDBP, 1 VAPB, and 1 FIG4). Clinic, Jacksonville, United States, 4MGH Institute of Health Peri-conversion data will be shown for the 4 C9orf72 Professions, Boston, United States, 5Biostatistics Center, MGH, carriers (3 ALS, 1 FTD) who have developed symptoms. Boston, United States Longitudinal strength, bulbar, and cognitive outcome data as well as direct biomarker comparison will be Live Poster Session A, December 9, 2020, 5:10 PM - 5:50 shown. DIALS enrollment and follow-up visits are PM ongoing. Background: Discussion: The validation of sensitive biofluid markers of inciting The DIALS Network dataset is composed of a growing disease pathology and clinical outcomes is crucial to number of pre-symptomatic ALS gene carriers, now detecting early disease, and to understanding the onset including several symptom converters.
    [Show full text]
  • Genetic Analysis of ALS Cases in the Isolated Island Population of Malta
    European Journal of Human Genetics (2021) 29:604–614 https://doi.org/10.1038/s41431-020-00767-9 ARTICLE Genetic analysis of ALS cases in the isolated island population of Malta 1,2 1,2 1 1 3 Rebecca Borg ● Maia Farrugia Wismayer ● Karl Bonavia ● Andrew Farrugia Wismayer ● Malcolm Vella ● 4 4 4 1,2 4 Joke J. F. A. van Vugt ● Brendan J. Kenna ● Kevin P. Kenna ● Neville Vassallo ● Jan H. Veldink ● Ruben J. Cauchi 1,2 Received: 6 May 2020 / Revised: 16 October 2020 / Accepted: 23 October 2020 / Published online: 7 January 2021 © The Author(s) 2020. This article is published with open access Abstract Genetic isolates are compelling tools for mapping genes of inherited disorders. The archipelago of Malta, a sovereign microstate in the south of Europe is home to a geographically and culturally isolated population. Here, we investigate the epidemiology and genetic profile of Maltese patients with amyotrophic lateral sclerosis (ALS), identified throughout a 2-year window. Cases were largely male (66.7%) with a predominant spinal onset of symptoms (70.8%). Disease onset occurred around mid-age (median age: 64 years, men; 59.5 years, female); 12.5% had familial ALS (fALS). Annual incidence rate – 1234567890();,: 1234567890();,: was 2.48 (95% CI 1.59 3.68) per 100,000 person-years. Male-to-female incidence ratio was 1.93:1. Prevalence was 3.44 (95% CI 2.01–5.52) cases per 100,000 inhabitants on 31st December 2018. Whole-genome sequencing allowed us to determine rare DNA variants that change the protein-coding sequence of ALS-associated genes.
    [Show full text]
  • Genetic Correlation Between Amyotrophic Lateral Sclerosis and Schizophrenia
    ARTICLE Received 6 Jul 2016 | Accepted 3 Feb 2017 | Published 21 Mar 2017 DOI: 10.1038/ncomms14774 OPEN Genetic correlation between amyotrophic lateral sclerosis and schizophrenia Russell L. McLaughlin1,2,*, Dick Schijven3,4,*, Wouter van Rheenen3, Kristel R. van Eijk3, Margaret O’Brien1, Project MinE GWAS Consortiumw, Schizophrenia Working Group of the Psychiatric Genomics Consortiumz, Rene´ S. Kahn4, Roel A. Ophoff4,5,6, An Goris7, Daniel G. Bradley2, Ammar Al-Chalabi8, Leonard H. van den Berg3, Jurjen J. Luykx3,4,9,**, Orla Hardiman2,** & Jan H. Veldink3,** We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P ¼ 1 Â 10 À 4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P ¼ 8.4 Â 10 À 7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies. 1 Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin DO2 DK07, Republic of Ireland.
    [Show full text]
  • Study Design and Pilot Analyses of a Large-Scale Whole Genome Sequencing Study in Amyotrophic Lateral Sclerosis
    bioRxiv preprint doi: https://doi.org/10.1101/152553; this version posted June 20, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Project MinE: study design and pilot analyses of a large-scale whole genome sequencing study in amyotrophic lateral sclerosis Project MinE ALS Sequencing Consortium* *A full list of consortium members appears at the end of this manuscript Correspondence Jan H. Veldink Department of Neurology, Brain Center Rudolf Magnus University Medical Center Utrecht Utrecht, The Netherlands [email protected] bioRxiv preprint doi: https://doi.org/10.1101/152553; this version posted June 20, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Abstract The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility of disease. We have therefore begun Project MinE, an international collaboration that seeks to analyse whole-genome sequence data of at least 15,000 ALS patients and 7,500 controls. Here, we report on the design of Project MinE and pilot analyses of newly whole-genome sequenced 1,264 ALS patients and 611 controls drawn from the Netherlands. As has become characteristic of sequencing studies, we find an abundance of rare genetic variation (minor allele frequency < 0.1%), the vast majority of which is absent in public data sets.
    [Show full text]
  • Project Mine: Study Design and Pilot Analyses of a Large-Scale Whole-Genome Sequencing Study in Amyotrophic Lateral Sclerosis
    This is a repository copy of Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/133970/ Version: Published Version Article: Project, M.A.S.C., van Rheenen, W., Pulit, S.L. et al. (36 more authors) (2018) Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis. European Journal of Human Genetics, 26 (10). pp. 1537-1546. ISSN 1018-4813 https://doi.org/10.1038/s41431-018-0177-4 Reuse This article is distributed under the terms of the Creative Commons Attribution (CC BY) licence. This licence allows you to distribute, remix, tweak, and build upon the work, even commercially, as long as you credit the authors for the original work. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ European Journal of Human Genetics https://doi.org/10.1038/s41431-018-0177-4 ARTICLE Project MinE: study design and pilot analyses of a large-scale whole- genome sequencing study in amyotrophic lateral sclerosis Project MinE ALS Sequencing Consortium Received: 12 December 2017 / Revised: 10 April 2018 / Accepted: 26 April 2018 © The Author(s) 2018.
    [Show full text]
  • 1 Enrichment of SARM1 Alleles Encoding Variants with Constitutively
    medRxiv preprint doi: https://doi.org/10.1101/2021.06.17.21258268; this version posted June 17, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders Jonathan Gilley 1, Oscar Jackson 1, Menelaos Pipis 2, Mehrdad A. Estiar 3,4, Ziv Gan-Or 3,4,5, Stephen A. Goutman 6, Matthew B. Harms 7, Julia Kaye 8, Leandro Lima 8, Queen Square Genomics 2, John Ravits 9, Guy A. Rouleau 3,4,5, Stephan Züchner 10, Mary M. Reilly 2 and Michael P. Coleman 1†. 1 John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK 2 Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, WC1N 3BG, UK 3 Department of Human Genetics, McGill University, Montreal, H3A 1A1, Canada 4 The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, H3A 2B4, Canada 5 Department of Neurology and Neurosurgery, McGill University, Montreal, H3A 1A1, Canada 6 Department of Neurology, University of Michigan, Ann Arbor, MI, USA 7 Institute for Genomic Medicine, Columbia University, New York, NY100332, USA 8 Finkbeiner lab, Center for Systems and Therapeutics, Bioinformatics Core, Institute of Data Science and Biotechnology, Gladstone Institutes, 1650 Owens Street, San Francisco, CA 94158, USA 9 Department of Neurosciences, University of California, San Diego, La Jolla, CA92093, USA 10 Dr.
    [Show full text]
  • Genome-Wide Identification of the Genetic Basis of Amyotrophic Lateral Sclerosis
    bioRxiv preprint doi: https://doi.org/10.1101/2020.11.14.382606; this version posted February 15, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Genome-wide Identification of the Genetic Basis of Amyotrophic Lateral Sclerosis Sai Zhang1,2,*, Johnathan Cooper-Knock3,*, Annika K. Weimer1,2, Minyi Shi1,2, Tobias Moll3, Calum Harvey3, Helia Ghahremani Nezhad3, John Franklin3, Cleide dos Santos Souza3, Cheng Wang4,5,6,7, Jingjing Li4,5,6,7, Eran Elhaik8, Chen Eitan9, Eran Hornstein9, Kevin P. Kenna10, Project MinE Sequencing Consortium, Jan Veldink10, Laura Ferraiuolo3, Pamela J. Shaw3 and Michael P. Snyder1,2 1Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA 2Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA 3Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK 4Department of Neurology, School of Medicine, University of California, San Francisco, CA, USA 5Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA 6Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA 7Parker Institute for Cancer Immunotherapy, University of California, San Francisco, CA, USA 8Department of Biology, Lund University, Lund, Sweden 9Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel 10Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands *These authors contributed equally to this work. Correspondence should be addressed to M.P.S. ([email protected]) 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.11.14.382606; this version posted February 15, 2021.
    [Show full text]
  • Genome-Wide Association Analyses Identify New Risk Variants and The
    Edinburgh Research Explorer Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis Citation for published version: Van Rheenen, W, Shatunov, A, Dekker, AM, Mclaughlin, RL, Diekstra, FP, Pulit, SL, Van Der Spek, RAA, Võsa, U, De Jong, S, Robinson, MR, Yang, J, Fogh, I, Van Doormaal, PT, Tazelaar, GHP, Koppers, M, Blokhuis, AM, Sproviero, W, Jones, AR, Kenna, KP, Van Eijk, KR, Harschnitz, O, Schellevis, RD, Brands, WJ, Medic, J, Menelaou, A, Vajda, A, Ticozzi, N, Lin, K, Rogelj, B, Vrabec, K, Ravnik-glava, M, Koritnik, B, Zidar, J, Leonardis, L, Grošelj, LD, Millecamps, S, Salachas, F, Meininger, V, De Carvalho, M, Pinto, S, Mora, JS, Rojas-garcía, R, Polak, M, Chandran, S, Colville, S, Swingler, R, Morrison, KE, Shaw, PJ, Hardy, J, Orrell, RW, Pittman, A, Sidle, K, Fratta, P, Malaspina, A, Topp, S, Petri, S, Abdulla, S, Drepper, C, Sendtner, M, Meyer, T, Ophoff, RA, Staats, KA, Wiedau-pazos, M, Lomen-hoerth, C, Van Deerlin, VM, Trojanowski, JQ, Elman, L, Mccluskey, L, Basak, AN, Tunca, C, Hamzeiy, H, Parman, Y, Meitinger, T, Lichtner, P, Radivojkov-blagojevic, M, Andres, CR, Maurel, C, Bensimon, G, Landwehrmeyer, B, Brice, A, Payan, CAM, Saker-delye, S, Dürr, A, Wood, NW, Tittmann, L, Lieb, W, Franke, A, Rietschel, M, Cichon, S, Nöthen, MM, Amouyel, P, Tzourio, C, Dartigues, J, Uitterlinden, AG, Rivadeneira, F, Estrada, K, Hofman, A, Curtis, C, Blauw, HM, Van Der Kooi, AJ, De Visser, M, Goris, A, Weber, M, Shaw, CE, Smith, BN, Pansarasa, O, Cereda, C, Del Bo, R, Comi, GP,
    [Show full text]
  • Project Mine: Study Design and Pilot Analyses of a Large-Scale Whole-Genome Sequencing Study in Amyotrophic Lateral Sclerosis [Preprint]
    University of Massachusetts Medical School eScholarship@UMMS University of Massachusetts Medical School Faculty Publications 2017-06-20 Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis [preprint] Project MinE Consortium Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/faculty_pubs Part of the Genetic Phenomena Commons, Genetics Commons, Genomics Commons, and the Nervous System Diseases Commons Repository Citation Project MinE Consortium, Van Rheenen W, Kenna KP, Landers JE, Veldink JH. (2017). Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis [preprint]. University of Massachusetts Medical School Faculty Publications. https://doi.org/ 10.1101/152553. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1533 Creative Commons License This work is licensed under a Creative Commons Attribution-No Derivative Works 4.0 License. This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in University of Massachusetts Medical School Faculty Publications by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. bioRxiv preprint first posted online Jun. 20, 2017; doi: http://dx.doi.org/10.1101/152553. The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-ND 4.0 International license. Project MinE: study design and pilot analyses of a large-scale whole genome sequencing study in amyotrophic lateral sclerosis Project MinE ALS Sequencing Consortium* *A full list of consortium members appears at the end of this manuscript Correspondence Jan H.
    [Show full text]