TY - JOUR
T1 - Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis
AU - Hop, Paul J.
AU - Kooyman, Maarten
AU - Kenna, Brendan J.
AU - Zwamborn, Ramona A.J.
AU - van Eijk, Kristel R.
AU - Wang, Yan
AU - van Dijk, Charlotte H.
AU - Bekema, Erwin
AU - van Rheenen, Wouter
AU - Beele, Paul
AU - van Vugt, Joke J.F.A.
AU - de Carvalho, Mamede
AU - van den Berg, Leonard H.
AU - Van Damme, Philip
AU - Smith, Bradley N.
AU - Khleifat, Ahmad Al
AU - Iacoangeli, Alfredo
AU - Cooper-Knock, Johnathan
AU - Smith, Bradley N.
AU - Topp, Simon
AU - van der Kooi, Anneke J.
AU - Fominykh, Vera
AU - Drory, Vivian
AU - Lerner, Yossef
AU - Shovman, Yehuda
AU - Rowe, Dominic B.
AU - Williams, Kelly L.
AU - McLaughlin, Russell L.
AU - Hurt, Jessica
AU - Huang, Yunfeng
AU - Chen, Chia Yen
AU - Tsai, Ellen
AU - Runz, Heiko
AU - Aronica, Eleonora
AU - Groen, Ewout J.N.
AU - van Es, Michael A.
AU - Pasterkamp, R. Jeroen
AU - Farhan, Sali M.K.
AU - Garton, Fleur C.
AU - McRae, Allan F.
AU - McCombe, Pamela A.
AU - Henderson, Robert D.
AU - Fan, Dongsheng
AU - Šlachtová, Lenka
AU - Høyer, Helle
AU - Nishimura, Agnes L.
AU - Van Damme, Philip
AU - van den Berg, Leonard H.
AU - Kenna, Kevin P.
AU - Veldink, Jan H.
N1 - Publisher Copyright:
© The Author(s) 2026.
PY - 2026/4
Y1 - 2026/4
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105035360014
U2 - 10.1038/s41588-026-02535-9
DO - 10.1038/s41588-026-02535-9
M3 - Article
C2 - 41917433
AN - SCOPUS:105035360014
SN - 1061-4036
VL - 58
SP - 717
EP - 725
JO - Nature genetics
JF - Nature genetics
IS - 4
ER -