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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. -
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. -
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. -
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. -
2018 National ALS Registry Annual Meeting Executive Summary
ATSDR’s Annual ALS Surveillance Meeting Summary Report August 1-2, 2017 2018 National ALS Registry Annual Meeting Executive Summary The cause(s) of ALS (Amyotrophic Lateral Sclerosis) remain unknown for 90-95 percent of those diagnosed with the disease and there is still no cure. The Agency for Toxic Substances and Disease Registry (ATSDR) established the National ALS Registry to determine how many people in the US are living with ALS, to describe the demographics of ALS patients, and most importantly to examine the risk factors for ALS. Although the Registry’s primary purpose is to capture cases of ALS, the Registry does a lot more than just count cases. The Registry is also: Funding ALS research, Collecting specimens from Registry enrollees through the National ALS Biorepository, Connecting patients with researchers recruiting for ALS clinical trials or epidemiological studies, Obtaining etiologic data from Registry enrollees through 17 different online risk factor modules such as occupational history, military history, residential history, history of traumatic brain injury (TBI), Providing data and biospecimens to scientists to further ALS research. The National ALS Registry Annual Meeting was held in Atlanta on August 7-8, 2018. There were 51 attendees, including persons living with ALS, neurologists, researchers, representatives of national ALS organizations, representatives of pharmaceutical companies, Registry staff, and other ALS experts. Background, Methodology, and State of the Registry Because ALS is a non-notifiable condition, CDC does not receive reports from states of the occurrence of ALS, as it does for most communicable diseases. The novel methodology developed by ATSDR for identifying newly diagnosed ALS cases uses data from national administrative databases (i.e., Medicare and the Veterans Administration) in addition to the information entered into the online Registry web portal by persons living with ALS. -
Group Statement
May 25, 2021 ALS Organizations Double Down on Their Support for Reintroduced Legislation That Will Accelerate Research and Encourage Access to Critical Investigational Therapies for Those Living with ALS. Today, leaders in the House of Representatives and Senate reintroduced the Accelerating Access to Critical Therapies for ALS Act. The ALS Association, I AM ALS, and the Muscular Dystrophy Association (MDA) endorse the revised legislation with this statement: “The Accelerating Access to Critical Therapies (ACT) for ALS Act builds new pathways to fund early access to ALS investigational therapies, accelerates ALS and rare neurodegenerative disease therapeutic development through a public-private partnership, and increases research on, and development of, interventions for rare neurodegenerative diseases through a new Food and Drug Administration (FDA) research grants program. The ALS Association, I AM ALS, and the Muscular Dystrophy Association endorse this legislation that is a paradigm shift in how therapeutic development, access to treatments, and research has been approached in a fatal, fast- progressing disease like ALS. The ACT for ALS will authorize $100 million a year over a five-year period to: (1) create a new grant program that funds access to investigational ALS treatments currently in development from small biotechnology companies for those patients who cannot participate in clinical trials, while concurrently supporting a research objective on how these investigational treatments impact the disease; (2) establish a Health -
Drug Development for Amyotrophic Lateral Sclerosis Guidance for Industry
Drug Development for Amyotrophic Lateral Sclerosis Guidance for Industry August 2017 Contents I. INTRODUCTION ................................................................................................................ 1 II. BACKGROUND ................................................................................................................... 2 III. BENEFIT RISK...................................................................................................................... 5 A. General comments .................................................................................................................. 5 B. Evidence of patient and caregiver preferences ....................................................................... 5 C. Implications of patient risk/benefit preferences in ALS ......................................................... 7 1. Alternative endpoints........................................................................................................... 7 2. Placebo control arm ............................................................................................................. 8 3. Threshold for statistical significance ................................................................................... 9 4. Method of delivery ............................................................................................................ 10 5. Role of expanded access and accelerated approval ........................................................... 11 6. Patient protection and need for informed -
A Er the Wildly Successful Ice Bucket Challenge
RESEARCH FEBRUARY/MARCH 2015 BY GINA SHAW Azer the Wildly Successful Ice Bucket Challenge ~e Ice Bucket Challenge raised big bucks on social media. Now, the ALS Association tells us where that cold, hard cash is going. As snowstorms and icy winds batter much of the country, it's hard to imagine willingly pouring a bucket of ice water over your head for any reason. But last August—when temperatures were much more forgiving—that's exactly what about 3 million people did. In an astonishing example of the power of social media, a July 31 dare from former Boston College baseball player Pete Frates, who was diagnosed with amyotrophic lateral sclerosis (ALS) in 2012, quickly went viral. The dare? Dump ice water on your head within 24 hours of being challenged or donate $100 (or whatever amount you could afford) to the ALS Association or another organization supporting ALS research. Pretty soon, the Ice Bucket Challenge meant dumping ice on your head and donating money, and everyone from your neighbor's preschooler to Bill Gates (with a custom-built ice douser), Oprah Winfrey, Jon Bon Jovi, and entire casts of Broadway shows were doing it—and posting their videos online. Even 86-year-old Ethel Kennedy took the challenge. (President Obama donated but declined the ice; actor Patrick Stewart posted a video of himself writing a check.) In La Jolla, CA, prominent ALS researcher Don Cleveland, PhD, who pioneered a novel therapy that turns off the defective genes that contribute to neurodegenerative diseases, watched the online commotion with skepticism. -
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. -
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. -
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. -
The Ice Bucket Challenge Chatter the Campaign Went Viral Who's Talking
TREATO: AFTER THE ALS ICE BUCKET CHALLENGE, WHAT IS THE HEALTH CONSUMER SAYING? Last summer’s ALS Ice Bucket Challenge was one of the most successful social media campaigns of all-time. Millions dumped a bucket of ice water on their head to promote awareness of the disease amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's Disease) and encourage donations to the ALS Association. Round Rock High School Dragon Band - photo by Henry Huey The campaign went viral More than 1billion 2.4 views million + videos posted to Watch Bill Gates ice #donate bucket challenge! $220 #ALS @alsassociation million raised Promoting awareness & AUGUST So what did the health consumer really think of such a grand campaign? With August creeping closer, will we see the same social virality that 1 2015 consumed YouTube and Facebook a year earlier? Online activity Discussions about ALS over time % Posts Monthly Although campaign sustainability was short, conversations still remain stead- ily higher than a year ago. 4/1/2014 7/1/2014 10/1/2014 1/1/2015 4/1/2015 ALS discussions grew by close to 6x the normal activity from July through August, a reflection the effectiveness of the ALS campaign Discussions about ice bucket challenge and ALS over time 35% Almost 30% of the ALS 30% discussions last August were 25% 20% about the ice bucket challenge. 15% The conversations then dropped 10% but we are beginning to see a 5% rise again this June. 0% Who's talking? 44% of all patients discussing ALS The percentage of caregivers are within the 30-49 age group, in talking about ALS is considerably contrast to a disease that is most higher than with other conditions prominent in the 50+ age group.