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

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.

Metadata

Item Type:	Article
Authors/Creators:	Hop, P.J. https://orcid.org/0000-0002-9007-7436 Kooyman, M. https://orcid.org/0000-0002-9023-5617 Kenna, B.J. https://orcid.org/0000-0001-7591-2221 Zwamborn, R.A.J. van Eijk, K.R. Wang, Y. van Dijk, C.H. https://orcid.org/0009-0003-2503-0038 Bekema, E. van Rheenen, W. https://orcid.org/0000-0002-5860-1533 Beele, P. https://orcid.org/0000-0003-0478-0836 van Vugt, J.J.F.A. https://orcid.org/0000-0002-4161-4004 Van Damme, P. van den Berg, L.H. de Carvalho, M. Smith, B.N. Khleifat, A.A. https://orcid.org/0000-0002-7406-9831 Iacoangeli, A. https://orcid.org/0000-0002-5280-5017 Cooper-Knock, J. https://orcid.org/0000-0002-0873-8689 Smith, B.N. https://orcid.org/0000-0002-6980-2453 Topp, S. https://orcid.org/0000-0002-5200-3284 van der Kooi, A.J. Fominykh, V. https://orcid.org/0000-0001-5490-2390 Drory, V. Lerner, Y. Shovman, Y. https://orcid.org/0000-0003-1961-7695 Rowe, D.B. Williams, K.L. https://orcid.org/0000-0001-6319-9473 McLaughlin, R.L. https://orcid.org/0000-0003-3915-2135 Hurt, J. Huang, Y. https://orcid.org/0000-0003-2120-3328 Chen, C.-Y. https://orcid.org/0000-0001-9548-5597 Tsai, E. https://orcid.org/0000-0002-5625-1189 Runz, H. https://orcid.org/0000-0002-2133-7345 Aronica, E. https://orcid.org/0000-0002-3542-3770 Groen, E.J.N. https://orcid.org/0000-0002-2330-9444 van Es, M.A. https://orcid.org/0000-0002-7709-5883 Pasterkamp, R.J. https://orcid.org/0000-0003-1631-6440 Farhan, S.M.K. Garton, F.C. McRae, A.F. McCombe, P.A. Henderson, R.D. Fan, D. Šlachtová, L. https://orcid.org/0000-0002-8013-728X Høyer, H. https://orcid.org/0000-0002-5445-0520 Nishimura, A.L. Cauchi, R.J. https://orcid.org/0000-0001-6150-1608 Brylev, L. Rogelj, B. https://orcid.org/0000-0003-3898-1943 Koritnik, B. https://orcid.org/0000-0002-5083-8261 Zidar, J. Salas, T. Mora Pardina, J.S. Gotkine, M. https://orcid.org/0000-0003-2541-6232 Povedano, M. Corcia, P. Vourc’h, P. Couratier, P. Weber, M. https://orcid.org/0000-0002-5538-9274 Kiernan, M.C. Pamphlett, R. Blair, I.P. de Carvalho, M. https://orcid.org/0000-0001-7556-0158 Başak, N.A. https://orcid.org/0000-0001-6977-2517 Ingre, C. Andersen, P.M. https://orcid.org/0000-0003-0094-5429 Zinman, L. Rogaeva, E. https://orcid.org/0000-0002-2852-0329 MacKenzie, I.R. https://orcid.org/0000-0003-3875-2972 Dupre, N. Rouleau, G.A. https://orcid.org/0000-0001-8403-1418 Traynor, B.J. Ticozzi, N. https://orcid.org/0000-0001-5963-7426 Chiò, A. Silani, V. https://orcid.org/0000-0002-7698-3854 Hardiman, O. Phatnani, H. Harms, M.B. https://orcid.org/0000-0002-3395-1633 Dalgard, C.L. https://orcid.org/0000-0003-2025-8239 Glass, J.D. https://orcid.org/0000-0002-3295-4971 Landers, J.E. https://orcid.org/0000-0001-8084-5043 Van Damme, P. https://orcid.org/0000-0002-4010-2357 Morrison, K.E. https://orcid.org/0000-0003-0216-5717 Shaw, P.J. https://orcid.org/0000-0002-8925-2567 Shaw, C.E. Al-Chalabi, A. https://orcid.org/0000-0002-4924-7712 van den Berg, L.H. https://orcid.org/0000-0002-6559-3965 Kenna, K.P. https://orcid.org/0009-0001-2712-7218 Veldink, J.H. https://orcid.org/0000-0001-5572-9657
Copyright, Publisher and Additional Information:	© 2026 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords:	Project MinE ALS sequencing Consortium; NYGC ALS Consortium; FALS sequencing Consortium; GTAC Consortium
Dates:	Accepted: 22 January 2026 Published (online): 31 March 2026 Published: April 2026
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Date Deposited:	16 Apr 2026 09:49
Last Modified:	16 Apr 2026 09:49
Published Version:	https://doi.org/10.1038/s41588-026-02535-9
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41588-026-02535-9
Related URLs:	PubMed URL Dataset
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:240085