Accès ouvert déclaré
2026
article
Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis
Paul J. Hop, Maarten Kooyman, Brendan Kenna, Ramona A.J. Zwamborn, Kristel R. van Eijk, Y Wang, C G M Van Dijk, Erwin Bekema, Wouter van Rheenen, Paul Beele, Joke J.F.A. van Vugt, Mamede de Carvalho, Leonard H. van den Berg, Philip Van Damme, Bradley Smith, Ahmad Al Khleifat, Alfredo Iacoangeli, Johnathan Cooper-Knock, Simon Topp, Anneke J. van der Kooi, Vera Fominykh, Vivian Drory, Yossef Lerner, Yehuda Shovman, Dominic B. Rowe, Kelly L. Williams, Russell L. McLaughlin, Jessica Hurt, Yunfeng Huang, Chia Yen Chen, Ellen Tsai, Heiko Runz, Eleonora Aronica, Ewout J.N. Groen, Michael A. van Es, R. Jeroen Pasterkamp, Sali M.K. Farhan, Fleur C. Garton, Allan F. McRae, Pamela A. McCombe, Robert D. Henderson, Dongsheng Fan, Lenka Šlachtová, Helle Høyer, Agnes L. Nishimura, Kevin P. Kenna, Jan H. Veldink, Project MinE ALS Sequencing Consortium, NYGC ALS Consortium, FALS Sequencing Consortium, GTAC Consortium, Neurogenetica, Brain, KNO Onderzoek, TN groep Kenna, Neurologen, Neuromuscular Disorders, Opleiding Neurologie, Projectafdeling ALS, Pathologie, Projectafdeling SvS, Neurochirurgen, Programmabureau Zorg van Morgen, Translational Neuroscience, Regenerative Medicine and Stem Cells, Genetic Risks
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Le résumé fourni par la source
Amyotrophic lateral sclerosis (ALS) is a heritable disorder where rare variants with low-to-moderate penetrance are thought to dominate genetic risk. To identify such rare variants, we harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases. Rare variant analyses identified several new risk genes, with replication confirming association of YKT6 and supporting HTR3C, GBGT1 and KNTC1. We also provide strong, independent validation for genes with limited previous evidence: ARPP21, DNAJC7 and CFAP410. Notably, in ARPP21, we identified a new high-effect variant (p.P747L) and confirmed that p.P563L is an ALS-associated variant leading to an aggressive disease course. Beyond new discoveries, our analyses largely recapitulated the known genetic architecture of ALS, identifying risk variants in over 20% of cases and supporting a cumulative oligogenic risk model. These findings highlight new translational targets and show that rare variant analyses capture substantially more genetic risk than common variant genome-wide association studies.
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Les sujets associés
Amyotrophic Lateral Sclerosis ResearchHereditary Neurological DisordersGenetic Neurodegenerative Diseases