| Title: | Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis |
| Journal: | Nature Genetics |
| Published: | 31 Mar 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41917433/ |
| DOI: | https://doi.org/10.1038/s41588-026-02535-9 |
Publication 18150
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
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.</p>
13 Keywords
- Amyotrophic Lateral Sclerosis
- Case-Control Studies
- Cohort Studies
- Exome
- Exome Sequencing
- Female
- Genetic Predisposition to Disease
- Genetic Variation
- Genome-Wide Association Study
- Humans
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
85 Authors
- Paul J. Hop
- Maarten Kooyman
- Brendan J. Kenna
- Ramona A. J. Zwamborn
- Kristel R. van Eijk
- Yan Wang
- Charlotte H. van Dijk
- Erwin Bekema
- Wouter van Rheenen
- Paul Beele
- Joke J. F. A. van Vugt
- Ahmad Al Khleifat
- Alfredo Iacoangeli
- Johnathan Cooper-Knock
- Bradley N. Smith
- 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
- Ruben J. Cauchi
- Lev Brylev
- Boris Rogelj
- Blaž Koritnik
- Janez Zidar
- Teresa Salas
- Jesus S. Mora Pardina
- Marc Gotkine
- Monica Povedano
- Philippe Corcia
- Patrick Vourc'h
- Philippe Couratier
- Markus Weber
- Matthew C. Kiernan
- Roger Pamphlett
- Ian P. Blair
- Mamede de Carvalho
- Nazli A. Başak
- Caroline Ingre
- Peter M. Andersen
- Lorne Zinman
- Ekaterina Rogaeva
- Ian R. MacKenzie
- Nicolas Dupre
- Guy A. Rouleau
- Bryan J. Traynor
- Nicola Ticozzi
- Adriano Chiò
- Vincenzo Silani
- Orla Hardiman
- Hemali Phatnani
- Matthew B. Harms
- Clifton L. Dalgard
- Jonathan D. Glass
- John E. Landers
- Philip Van Damme
- Karen E. Morrison
- Pamela J. Shaw
- Chris E. Shaw
- Ammar Al-Chalabi
- Leonard H. van den Berg
- Kevin P. Kenna
- Jan H. Veldink
1 Application
| Application ID | Title |
|---|---|
| 48361 | Genome wide association analysis of Amyotrophic Lateral Sclerosis (ALS) |
Enabling scientific discoveries that improve human health