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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.

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.

SUBMITTER: van Rheenen W

PROVIDER: S-EPMC8648564 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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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.

van Rheenen Wouter W van der Spek Rick A A RAA Bakker Mark K MK van Vugt Joke J F A JJFA Hop Paul J PJ Zwamborn Ramona A J RAJ de Klein Niek N Westra Harm-Jan HJ Bakker Olivier B OB Deelen Patrick P Shireby Gemma G Hannon Eilis E Moisse Matthieu M Baird Denis D Restuadi Restuadi R Dolzhenko Egor E Dekker Annelot M AM Gawor Klara K Westeneng Henk-Jan HJ Tazelaar Gijs H P GHP van Eijk Kristel R KR Kooyman Maarten M Byrne Ross P RP Doherty Mark M Heverin Mark M Al Khleifat Ahmad A Iacoangeli Alfredo A Shatunov Aleksey A Ticozzi Nicola N Cooper-Knock Johnathan J Smith Bradley N BN Gromicho Marta M Chandran Siddharthan S Pal Suvankar S Morrison Karen E KE Shaw Pamela J PJ Hardy John J Orrell Richard W RW Sendtner Michael M Meyer Thomas T Başak Nazli N van der Kooi Anneke J AJ Ratti Antonia A Fogh Isabella I Gellera Cinzia C Lauria Giuseppe G Corti Stefania S Cereda Cristina C Sproviero Daisy D D'Alfonso Sandra S Sorarù Gianni G Siciliano Gabriele G Filosto Massimiliano M Padovani Alessandro A Chiò Adriano A Calvo Andrea A Moglia Cristina C Brunetti Maura M Canosa Antonio A Grassano Maurizio M Beghi Ettore E Pupillo Elisabetta E Logroscino Giancarlo G Nefussy Beatrice B Osmanovic Alma A Nordin Angelica A Lerner Yossef Y Zabari Michal M Gotkine Marc M Baloh Robert H RH Bell Shaughn S Vourc'h Patrick P Corcia Philippe P Couratier Philippe P Millecamps Stéphanie S Meininger Vincent V Salachas François F Mora Pardina Jesus S JS Assialioui Abdelilah A Rojas-García Ricardo R Dion Patrick A PA Ross Jay P JP Ludolph Albert C AC Weishaupt Jochen H JH Brenner David D Freischmidt Axel A Bensimon Gilbert G Brice Alexis A Durr Alexandra A Payan Christine A M CAM Saker-Delye Safa S Wood Nicholas W NW Topp Simon S Rademakers Rosa R Tittmann Lukas L Lieb Wolfgang W Franke Andre A Ripke Stephan S Braun Alice A Kraft Julia J Whiteman David C DC Olsen Catherine M CM Uitterlinden Andre G AG Hofman Albert A Rietschel Marcella M Cichon Sven S Nöthen Markus M MM Amouyel Philippe P Traynor Bryan J BJ Singleton Andrew B AB Mitne Neto Miguel M Cauchi Ruben J RJ Ophoff Roel A RA Wiedau-Pazos Martina M Lomen-Hoerth Catherine C van Deerlin Vivianna M VM Grosskreutz Julian J Roediger Annekathrin A Gaur Nayana N Jörk Alexander A Barthel Tabea T Theele Erik E Ilse Benjamin B Stubendorff Beatrice B Witte Otto W OW Steinbach Robert R Hübner Christian A CA Graff Caroline C Brylev Lev L Fominykh Vera V Demeshonok Vera V Ataulina Anastasia A Rogelj Boris B Koritnik Blaž B Zidar Janez J Ravnik-Glavač Metka M Glavač Damjan D Stević Zorica Z Drory Vivian V Povedano Monica M Blair Ian P IP Kiernan Matthew C MC Benyamin Beben B Henderson Robert D RD Furlong Sarah S Mathers Susan S McCombe Pamela A PA Needham Merrilee M Ngo Shyuan T ST Nicholson Garth A GA Pamphlett Roger R Rowe Dominic B DB Steyn Frederik J FJ Williams Kelly L KL Mather Karen A KA Sachdev Perminder S PS Henders Anjali K AK Wallace Leanne L de Carvalho Mamede M Pinto Susana S Petri Susanne S Weber Markus M Rouleau Guy A GA Silani Vincenzo V Curtis Charles J CJ Breen Gerome G Glass Jonathan D JD Brown Robert H RH Landers John E JE Shaw Christopher E CE Andersen Peter M PM Groen Ewout J N EJN van Es Michael A MA Pasterkamp R Jeroen RJ Fan Dongsheng D Garton Fleur C FC McRae Allan F AF Davey Smith George G Gaunt Tom R TR Eberle Michael A MA Mill Jonathan J McLaughlin Russell L RL Hardiman Orla O Kenna Kevin P KP Wray Naomi R NR Tsai Ellen E Runz Heiko H Franke Lude L Al-Chalabi Ammar A Van Damme Philip P van den Berg Leonard H LH Veldink Jan H JH

Nature genetics 20211206 12

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 (M ...[more]

PMID: 34873335

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Project description:Amyotrophic lateral sclerosis is a motor neuron degenerative disease that is also known as Lou Gehrig's disease in the United States, Charcot's disease in France, and motor neuron disease in the UK. The loss of motor neurons causes muscle wasting, paralysis, and eventually death, which is commonly related to respiratory failure, within 3-5 years after onset of the disease. Although there are a limited number of drugs approved for amyotrophic lateral sclerosis, they have had little success at treating the associated symptoms, and they cannot reverse the course of motor neuron degeneration. Thus, there is still a lack of effective treatment for this debilitating neurodegenerative disorder. Stem cell therapy for amyotrophic lateral sclerosis is a very attractive strategy for both basic and clinical researchers, particularly as transplanted stem cells and stem cell-derived neural progenitor/precursor cells can protect endogenous motor neurons and directly replace the lost or dying motor neurons. Stem cell therapies may also be able to re-establish the motor control of voluntary muscles. Here, we review the recent progress in the use of neural stem cells and neural progenitor cells for the treatment of amyotrophic lateral sclerosis. We focus on MN progenitor cells derived from fetal central nervous system tissue, embryonic stem cells, and induced pluripotent stem cells. In our recent studies, we found that transplanted human induced pluripotent stem cell-derived motor neuron progenitors survive well, differentiate into motor neurons, and extend axons into the host white matter, not only in the rostrocaudal direction, but also along motor axon tracts towards the ventral roots in the immunodeficient rat spinal cord. Furthermore, the significant motor axonal extension after neural progenitor cell transplantation in amyotrophic lateral sclerosis models demonstrates that motor neuron replacement therapy could be a promising therapeutic strategy for amyotrophic lateral sclerosis, particularly as a variety of stem cell derivatives, including induced pluripotent stem cells, are being considered for clinical trials for various diseases.

Project description:BackgroundAmyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND) is a fatal disease associated with rapidly progressive disability, for which no definitive treatment as yet exists. Current treatment regimens largely focus on relieving symptoms to improve the quality of life of those affected. Based on data from preclinical studies, cell-based therapy is a promising treatment for ALS/MND.ObjectivesTo assess the effects of cell-based therapy for people with ALS/MND, compared with placebo or no additional treatment.Search methodsOn 21 June 2016, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched two clinical trials' registries for ongoing or unpublished studies.Selection criteriaWe planned to include randomised controlled trials (RCTs), quasi-RCTs and cluster RCTs that assigned people with ALS/MND to receive cell-based therapy versus a placebo or no additional treatment. Co-interventions were allowable, provided that they were given to each group equally.Data collection and analysisWe followed standard Cochrane methodology.Main resultsNo studies were eligible for inclusion in the review. We identified four ongoing trials.Authors' conclusionsCurrently, there is a lack of high-quality evidence to guide practice on the use of cell-based therapy to treat ALS/MND.We need large, prospective RCTs to establish the efficacy of cellular therapy and to determine patient-, disease- and cell treatment-related factors that may influence the outcome of cell-based therapy. The major goals of future research should be to determine the appropriate cell source, phenotype, dose, and route of delivery, as these will be key elements in designing an optimal cell-based therapy programme for people with ALS/MND. Future research should also explore novel treatment strategies, including combinations of cellular therapy and standard or novel neuroprotective agents, to find the best possible approach to prevent or reverse the neurological deficit in ALS/MND, and to prolong survival in this debilitating and fatal condition.

Dataset Information

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

Publications

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

Similar Datasets

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