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DOI 10.1038/s41588-026-02535-9

Медицинская библиотека · Nature genetics · 2026

Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis.

Hop Paul J, Kooyman Maarten, Kenna Brendan J, Zwamborn Ramona A J, van Eijk Kristel R, Wang Yan, van Dijk Charlotte H, Bekema Erwin, van Rheenen Wouter, Beele Paul, van Vugt Joke J F A, Project MinE ALS sequencing Consortium, NYGC ALS Consortium, FALS sequencing Consortium, GTAC Consortium, Khleifat Ahmad Al, Iacoangeli Alfredo, Cooper-Knock Johnathan, Smith Bradley N, Topp Simon, van der Kooi Anneke J, Fominykh Vera, Drory Vivian, Lerner Yossef, Shovman Yehuda, Rowe Dominic B, Williams Kelly L, McLaughlin Russell L, Hurt Jessica, Huang Yunfeng, Chen Chia-Yen, Tsai Ellen, Runz Heiko, Aronica Eleonora, Groen Ewout J N, van Es Michael A, Pasterkamp R Jeroen, Farhan Sali M K, Garton Fleur C, McRae Allan F, McCombe Pamela A, Henderson Robert D, Fan Dongsheng, Šlachtová Lenka, Høyer Helle, Nishimura Agnes L, Cauchi Ruben J, Brylev Lev, Rogelj Boris, Koritnik Blaž, Zidar Janez, Salas Teresa, Mora Pardina Jesus S, Gotkine Marc, Povedano Monica, Corcia Philippe, Vourc'h Patrick, Couratier Philippe, Weber Markus, Kiernan Matthew C, Pamphlett Roger, Blair Ian P, de Carvalho Mamede, Başak Nazli A, Ingre Caroline, Andersen Peter M, Zinman Lorne, Rogaeva Ekaterina, MacKenzie Ian R, Dupre Nicolas, Rouleau Guy A, Traynor Bryan J, Ticozzi Nicola, Chiò Adriano, Silani Vincenzo, Hardiman Orla, Phatnani Hemali, Harms Matthew B, Dalgard Clifton L, Glass Jonathan D, Landers John E, Van Damme Philip, Morrison Karen E, Shaw Pamela J, Shaw Chris E, Al-Chalabi Ammar, van den Berg Leonard H, Kenna Kevin P, Veldink Jan H

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Аннотация

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.

Для цитирования: Hop Paul J, Kooyman Maarten, Kenna Brendan J, Zwamborn Ramona A J, van Eijk Kristel R, Wang Yan, van Dijk Charlotte H, Bekema Erwin, van Rheenen Wouter, Beele Paul, van Vugt Joke J F A, Project MinE ALS sequencing Consortium, NYGC ALS Consortium, FALS sequencing Consortium, GTAC Consortium, Khleifat Ahmad Al, Iacoangeli Alfredo, Cooper-Knock Johnathan, Smith Bradley N, Topp Simon, van der Kooi Anneke J, Fominykh Vera, Drory Vivian, Lerner Yossef, Shovman Yehuda, Rowe Dominic B, Williams Kelly L, McLaughlin Russell L, Hurt Jessica, Huang Yunfeng, Chen Chia-Yen, Tsai Ellen, Runz Heiko, Aronica Eleonora, Groen Ewout J N, van Es Michael A, Pasterkamp R Jeroen, Farhan Sali M K, Garton Fleur C, McRae Allan F, McCombe Pamela A, Henderson Robert D, Fan Dongsheng, Šlachtová Lenka, Høyer Helle, Nishimura Agnes L, Cauchi Ruben J, Brylev Lev, Rogelj Boris, Koritnik Blaž, Zidar Janez, Salas Teresa, Mora Pardina Jesus S, Gotkine Marc, Povedano Monica, Corcia Philippe, Vourc'h Patrick, Couratier Philippe, Weber Markus, Kiernan Matthew C, Pamphlett Roger, Blair Ian P, de Carvalho Mamede, Başak Nazli A, Ingre Caroline, Andersen Peter M, Zinman Lorne, Rogaeva Ekaterina, MacKenzie Ian R, Dupre Nicolas, Rouleau Guy A, Traynor Bryan J, Ticozzi Nicola, Chiò Adriano, Silani Vincenzo, Hardiman Orla, Phatnani Hemali, Harms Matthew B, Dalgard Clifton L, Glass Jonathan D, Landers John E, Van Damme Philip, Morrison Karen E, Shaw Pamela J, Shaw Chris E, Al-Chalabi Ammar, van den Berg Leonard H, Kenna Kevin P, Veldink Jan H. Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis.. Nature genetics. 2026. DOI: 10.1038/s41588-026-02535-9.

Предметные рубрики MeSH

HumansAmyotrophic Lateral SclerosisGenetic Predisposition to DiseaseGenome-Wide Association StudyExomeGenetic VariationExome SequencingPolymorphism, Single Nucleotide
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