Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology,Nature Genetics

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Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
Nature Genetics ( IF 30.8 ) Pub Date : 2021-12-06 , DOI: 10.1038/s41588-021-00973-1
Wouter van Rheenen ₁ , Rick A A van der Spek ₁ , Mark K Bakker ₁ , Joke J F A van Vugt ₁ , Paul J Hop ₁ , Ramona A J Zwamborn ₁ , Niek de Klein ₂ , Harm-Jan Westra ₂ , Olivier B Bakker ₂ , Patrick Deelen _{2,

3} , Gemma Shireby ₄ , Eilis Hannon ₄ , Matthieu Moisse _{5,

6,

7} , Denis Baird _{8,

9} , Restuadi Restuadi ₁₀ , Egor Dolzhenko ₁₁ , Annelot M Dekker ₁ , Klara Gawor ₁ , Henk-Jan Westeneng ₁ , Gijs H P Tazelaar ₁ , Kristel R van Eijk ₁ , Maarten Kooyman ₁ , Ross P Byrne ₁₂ , Mark Doherty ₁₂ , Mark Heverin ₁₃ , Ahmad Al Khleifat ₁₄ , Alfredo Iacoangeli _{14,

15,

16} , Aleksey Shatunov ₁₄ , Nicola Ticozzi _{17,

18} , Johnathan Cooper-Knock ₁₉ , Bradley N Smith ₁₄ , Marta Gromicho ₂₀ , Siddharthan Chandran _{21,

22} , Suvankar Pal _{21,

22} , Karen E Morrison ₂₃ , Pamela J Shaw ₁₉ , John Hardy ₂₄ , Richard W Orrell ₂₅ , Michael Sendtner ₂₆ , Thomas Meyer ₂₇ , Nazli Başak ₂₈ , Anneke J van der Kooi ₂₉ , Antonia Ratti _{17,

30} , Isabella Fogh ₁₄ , Cinzia Gellera ₃₁ , Giuseppe Lauria _{32,

33} , Stefania Corti _{18,

34} , Cristina Cereda ₃₅ , Daisy Sproviero ₃₅ , Sandra D'Alfonso ₃₆ , Gianni Sorarù ₃₇ , Gabriele Siciliano ₃₈ , Massimiliano Filosto ₃₉ , Alessandro Padovani ₃₉ , Adriano Chiò _{40,

41} , Andrea Calvo _{40,

41} , Cristina Moglia _{40,

41} , Maura Brunetti ₄₀ , Antonio Canosa _{40,

41} , Maurizio Grassano ₄₀ , Ettore Beghi ₄₂ , Elisabetta Pupillo ₄₂ , Giancarlo Logroscino ₄₃ , Beatrice Nefussy ₄₄ , Alma Osmanovic _{45,

46} , Angelica Nordin ₄₇ , Yossef Lerner _{48,

49} , Michal Zabari _{48,

49} , Marc Gotkine _{48,

49} , Robert H Baloh _{50,

51} , Shaughn Bell _{50,

51} , Patrick Vourc'h _{52,

53} , Philippe Corcia _{53,

54} , Philippe Couratier _{55,

56} , Stéphanie Millecamps ₅₇ , Vincent Meininger ₅₈ , François Salachas _{57,

59} , Jesus S Mora Pardina ₆₀ , Abdelilah Assialioui ₆₁ , Ricardo Rojas-García ₆₂ , Patrick A Dion _{63,

64} , Jay P Ross _{63,

65} , Albert C Ludolph ₆₆ , Jochen H Weishaupt ₆₇ , David Brenner ₆₇ , Axel Freischmidt _{66,

68} , Gilbert Bensimon _{69,

70,

71,

72} , Alexis Brice ₇₃ , Alexandra Durr ₇₃ , Christine A M Payan ₆₉ , Safa Saker-Delye ₇₄ , Nicholas W Wood ₇₅ , Simon Topp ₁₄ , Rosa Rademakers ₇₆ , Lukas Tittmann ₇₇ , Wolfgang Lieb ₇₇ , Andre Franke ₇₈ , Stephan Ripke _{79,

80,

81} , Alice Braun ₈₁ , Julia Kraft ₈₁ , David C Whiteman ₈₂ , Catherine M Olsen ₈₂ , Andre G Uitterlinden _{83,

84} , Albert Hofman ₈₄ , Marcella Rietschel _{85,

86} , Sven Cichon _{87,

88,

89,

90} , Markus M Nöthen _{87,

88} , Philippe Amouyel ₉₁ , , , , , Bryan J Traynor _{92,

93} , Andrew B Singleton ₉₄ , Miguel Mitne Neto ₉₅ , Ruben J Cauchi ₉₆ , Roel A Ophoff _{97,

98,

99} , Martina Wiedau-Pazos ₁₀₀ , Catherine Lomen-Hoerth ₁₀₁ , Vivianna M van Deerlin ₁₀₂ , Julian Grosskreutz _{103,

104} , Annekathrin Roediger ₁₀₃ , Nayana Gaur ₁₀₃ , Alexander Jörk ₁₀₃ , Tabea Barthel ₁₀₃ , Erik Theele ₁₀₃ , Benjamin Ilse ₁₀₃ , Beatrice Stubendorff ₁₀₃ , Otto W Witte ₁₀₃ , Robert Steinbach ₁₀₃ , Christian A Hübner ₁₀₅ , Caroline Graff ₁₀₆ , Lev Brylev _{107,

108,

109} , Vera Fominykh _{107,

109} , Vera Demeshonok ₁₁₀ , Anastasia Ataulina ₁₀₇ , Boris Rogelj _{111,

112,

113} , Blaž Koritnik ₁₁₄ , Janez Zidar ₁₁₄ , Metka Ravnik-Glavač ₁₁₅ , Damjan Glavač ₁₁₆ , Zorica Stević ₁₁₇ , Vivian Drory _{44,

118} , Monica Povedano ₆₁ , Ian P Blair ₁₁₉ , Matthew C Kiernan ₁₂₀ , Beben Benyamin _{10,

121} , Robert D Henderson _{122,

123} , Sarah Furlong ₁₁₉ , Susan Mathers ₁₂₄ , Pamela A McCombe _{123,

125} , Merrilee Needham _{126,

127,

128} , Shyuan T Ngo _{122,

123,

125} , Garth A Nicholson _{119,

129,

130} , Roger Pamphlett ₁₃₁ , Dominic B Rowe ₁₁₉ , Frederik J Steyn _{123,

132} , Kelly L Williams ₁₁₉ , Karen A Mather _{133,

134} , Perminder S Sachdev _{133,

135} , Anjali K Henders ₁₀ , Leanne Wallace ₁₀ , Mamede de Carvalho ₂₀ , Susana Pinto ₂₀ , Susanne Petri ₄₅ , Markus Weber ₁₃₆ , Guy A Rouleau _{63,

64,

65} , Vincenzo Silani _{17,

18} , Charles J Curtis _{137,

138} , Gerome Breen _{137,

138} , Jonathan D Glass ₁₃₉ , Robert H Brown ₁₄₀ , John E Landers ₁₄₀ , Christopher E Shaw ₁₄ , Peter M Andersen ₄₇ , Ewout J N Groen ₁ , Michael A van Es ₁ , R Jeroen Pasterkamp ₁₄₁ , Dongsheng Fan ₁₄₂ , Fleur C Garton ₁₀ , Allan F McRae ₁₀ , George Davey Smith _{9,

143} , Tom R Gaunt _{9,

143} , Michael A Eberle ₁₁ , Jonathan Mill ₄ , Russell L McLaughlin ₁₂ , Orla Hardiman ₁₃ , Kevin P Kenna _{1,

141} , Naomi R Wray _{10,

125} , Ellen Tsai ₈ , Heiko Runz ₈ , Lude Franke ₂ , Ammar Al-Chalabi _{14,

144} , Philip Van Damme _{5,

6,

7} , Leonard H van den Berg ₁ , Jan H Veldink ₁

Affiliation

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK.
Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, Leuven, Belgium.
Laboratory of Neurobiology, VIB, Center for Brain & Disease Research, Leuven, Belgium.
Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
Translational Biology, Biogen, Boston, MA, USA.
MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, University of Bristol, Bristol, UK.
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Illumina, San Diego, CA, USA.
Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
National Institute for Health Research Biomedical Research Centre and Dementia Unit, South London and Maudsley NHS Foundation Trust and King's College London, London, UK.
Department of Neurology, Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano IRCCS, Milan, Italy.
Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
Instituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Euan MacDonald Centre for Motor Neurone Disease Research, Edinburgh, UK.
UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.
School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany.
Charité University Hospital, Humboldt University, Berlin, Germany.
Koç University, School of Medicine, KUTTAM-NDAL, Istanbul, Turkey.
Department of Neurology, Academic Medical Center, Amsterdam, the Netherlands.
Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
3rd Neurology Unit, Motor Neuron Diseases Center, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', MIlan, Italy.
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Genomic and Post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy.
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
Department of Neurosciences, University of Padova, Padova, Italy.
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
Neurologia 1, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
Laboratory of Neurological Diseases, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Department of Clinical Research in Neurology, University of Bari at 'Pia Fondazione Card G. Panico' Hospital, Bari, Italy.
Neuromuscular Diseases Unit, Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Department of Neurology, Hannover Medical School, Hannover, Germany.
Essener Zentrum für Seltene Erkrankungen (EZSE), University Hospital Essen, Essen, Germany.
Department of Clinical Sciences, Neurosciences, Umeå University, Umeå, Sweden.
Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Department of Neurology, the Agnes Ginges Center for Human Neurogenetics, Hadassah Medical Center, Jerusalem, Israel.
Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Neurology, Neuromuscular Division, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Service de Biochimie et Biologie Moléculaire, CHU de Tours, Tours, France.
UMR 1253, Université de Tours, Inserm, Tours, France.
Centre de référence sur la SLA, CHU de Tours, Tours, France.
Centre de référence sur la SLA, CHRU de Limoges, Limoges, France.
UMR 1094, Université de Limoges, Inserm, Limoges, France.
ICM, Institut du Cerveau, Inserm, CNRS, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Hôpital des Peupliers, Ramsay Générale de Santé, Paris, France.
Département de Neurologie, Centre de référence SLA Ile de France, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France.
ALS Unit, Hospital San Rafael, Madrid, Spain.
Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain.
MND Clinic, Neurology Department, Hospital de la Santa Creu i Sant Pau de Barcelona, Universitat Autonoma de Barcelona, Barcelona, Spain.
Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Department of Neurology, Ulm University, Ulm, Germany.
Division of Neurodegeneration, Department of Neurology, University Medicine Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
German Center for Neurodegenerative Diseases (DZNE) Ulm, Ulm, Germany.
Département de Pharmacologie Clinique, Hôpital de la Pitié-Salpêtrière, UPMC Pharmacologie, AP-HP, Paris, France.
Pharmacologie Sorbonne Université, Paris, France.
Institut du Cerveau, Paris Brain Institute ICM, Paris, France.
Laboratoire de Biostatistique, Epidémiologie Clinique, Santé Publique Innovation et Méthodologie (BESPIM), CHU-Nîmes, Nîmes, France.
Sorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Hôpital de la Pitié Salpêtrière, Paris, France.
Genethon, CNRS UMR, Evry, France.
Department of Clinical and Movement Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
Popgen Biobank and Institute of Epidemiology, Christian Albrechts-University Kiel, Kiel, Germany.
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany.
Cancer Control Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Department of Internal Medicine, Genetics Laboratory, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.
Department of Epidemiology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.
Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
Central Institute of Mental Health, Mannheim, Germany.
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Department of Genomics, Life and Brain Center, Bonn, Germany.
Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.
Institute of Neuroscience and Medicine INM-1, Research Center Juelich, Juelich, Germany.
INSERM UMR1167-RID-AGE LabEx DISTALZ-Risk Factors and Molecular Determinants of Aging-Related Diseases, University of Lille, Centre Hospitalier of the University of Lille, Institut Pasteur de Lille, Lille, France.
Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD, USA.
Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD, USA.
Universidade de São Paulo, São Paulo, Brazil.
Centre for Molecular Medicine and Biobanking and Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.
University Medical Center Utrecht, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, Utrecht, the Netherlands.
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Department of Neurology, University of California, San Francisco, CA, USA.
Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
Precision Neurology Unit, Department of Neurology, University Hospital Schleswig-Holstein, University of Luebeck, Luebeck, Germany.
Institute of Human Genetics, Jena University Hospital, Jena, Germany.
Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Department of Neurology, Bujanov Moscow Clinical Hospital, Moscow, Russia.
Moscow Research and Clinical Center for Neuropsychiatry of the Healthcare Department, Moscow, Russia.
Department of Functional Biochemistry of the Nervous System, Institute of Higher Nervous Activity and Neurophysiology Russian Academy of Sciences, Moscow, Russia.
ALS-Care Center, 'GAOORDI', Medical Clinic of the St. Petersburg, St. Petersburg, Russia.
Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia.
Biomedical Research Institute BRIS, Ljubljana, Slovenia.
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia.
Ljubljana ALS Centre, Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia.
Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Clinic of Neurology, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.
Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
Australian Centre for Precision Health and Allied Health and Human Performance, University of South Australia, Adelaide, South Australia, Australia.
Centre for Clinical Research, Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland, Australia.
Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
Calvary Health Care Bethlehem, Parkdale, Victoria, Australia.
Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
Fiona Stanley Hospital, Perth, Western Australia, Australia.
Notre Dame University, Fremantle, Western Australia, Australia.
Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University, Perth, Western Australia, Australia.
Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, New South Wales, Australia.
Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, New South Wales, Australia.
Discipline of Pathology and Department of Neuropathology, Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
The School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
Neuroscience Research Australia Institute, Randwick, New South Wales, Australia.
Neuropsychiatric Institute, the Prince of Wales Hospital, UNSW, Randwick, New South Wales, Australia.
Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland.
Social Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.
NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.
Department Neurology, Emory University School of Medicine, Atlanta, GA, USA.
Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Department of Neurology, Third Hospital, Peking University, Beijing, China.
Population Health Science, Bristol Medical School, Bristol, UK.
King's College Hospital, London, UK.

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.

中文翻译：

肌萎缩侧索硬化症的常见和罕见变异关联分析确定了具有不同遗传结构和神经元特异性生物学的 15 个风险位点

肌萎缩侧索硬化症 (ALS) 是一种致命的神经退行性疾病，一生中每 350 人中就有一人患病，并且对疾病缓解疗法的需求尚未得到满足。我们进行了一项跨祖先全基因组关联研究 (GWAS)，纳入了 29,612 名 ALS 患者和 122,656 名对照者，确定了 15 个风险位点。当与 8,953 名个体的全基因组测序（6,538 名患者，2,415 名对照）和大型皮层衍生表达数量性状基因座 (eQTL) 数据集 (MetaBrain) 相结合时，分析揭示了基因座特异性遗传结构，在该结构中，我们通过罕见的基因优先顺序排列基因变异、短串联重复或调控效应。ALS 相关风险位点与神经退行性谱系中的多种特征相同，但在大脑区域和细胞类型之间具有不同的富集模式。在从文献中获得的环境和生活方式风险因素中，孟德尔随机分析表明高胆固醇水平具有因果作用。所有 ALS 相关信号的组合揭示了囊泡介导的运输和自噬中扰动的作用，并为谷氨酸能神经元中细胞自主疾病的起始提供了证据。

更新日期：2021-12-06

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