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

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.

Authors

Institutions

Publication Details

Journal
Nature Genetics
Published
2026-03-31
DOI
https://doi.org/10.1038/s41588-026-02535-9
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Erwin Bekema, Maarten Kooyman, Helle Høyer, Jesús S. Mora Pardina et al.
Nature Genetics
Amyotrophic Lateral Sclerosis Research
article

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

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

Abstract

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.

Nature GeneticsVol. 58(4)
Université de Tours (FR), New York University Abu Dhabi (AE), Queen's University Belfast (GB), Montreal Neurological Institute and Hospital (CA), The University of Sydney (AU), Biogen (United States) (US), Allen Institute for Brain Science (US), Sunnybrook Health Science Centre (CA), Karolinska University Hospital (SE), Koç University (TR), University of Lisbon (PT), University of British Columbia (CA), Johns Hopkins University (US), Uniformed Services University of the Health Sciences (US), Emory University (US), University of Ljubljana (SI), Inserm (FR), The University of Queensland (AU), Queen Mary University of London (GB), University of Massachusetts Chan Medical School (US), King's College London (GB), University of Oslo (NO), University of Toronto (CA), University of Milan (IT), Utrecht University (NL), Hebrew University of Jerusalem (IL), University of Malta (MT), Peking University (CN), Trinity College Dublin (IE), Charles University (CZ), Columbia University Irving Medical Center (US), Royal Prince Alfred Hospital (AU), Tel Aviv Sourasky Medical Center (IL), Kantonsspital St. Gallen (CH), Hospital Universitario La Paz (ES), Ljubljana University Medical Centre (SI), Bellvitge University Hospital (ES), Health Sciences Centre (CA), University Medical Center (US), Karolinska Institutet (SE), Jožef Stefan Institute (SI), University Medical Center Utrecht (NL), UNSW Sydney (AU), Centre Hospitalier Universitaire de Tours (FR), Amsterdam Neuroscience (NL), Occupational Cancer Research Centre (CA), Telemark Hospital (NO), IRCCS Istituto Auxologico Italiano (IT), National Institute on Aging (US), Peking University Third Hospital (CN), New York Genome Center (US), Amsterdam University Medical Centers (NL), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Hospital Universitario San Rafael (ES), Hôpital Dupuytren (FR), Ferrari (Italy) (IT), Université Laval (CA), McGill University (CA), University of Turin (IT), Columbia University (US), Neuroscience Research Australia (AU), University of Amsterdam (NL), Umeå University (SE), Gojo (France) (FR), University of Sheffield (GB), Macquarie University (AU), KU Leuven (BE)
ALS Association, Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Openalex Percentile: Top 29%
Amyotrophic Lateral Sclerosis Research
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.