| Title: | Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis |
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| Authors: | ID Hop, Paul J. (Author)
ID Rogelj, Boris (Author)
ID Koritnik, Blaž (Author)
ID Zidar, Janez (Author)
ID Veldink, Jan H. (Author), et al. |
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| Files: |  PDF - Presentation file, download (22,71 MB)
MD5: 292783084A594D3619C3EDABEC19C02E
 URL - Source URL, visit https://www.nature.com/articles/s41588-026-02535-9
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| Language: | English |
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| Typology: | 1.01 - Original Scientific Article |
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| Organization: |  UKC LJ - Ljubljana University Medical Centre
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| 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. |
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| Keywords: | genetics, neuroscience, rare variant analysis, amyotrophic lateral sclerosis (ALS), genetic risk factors |
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| Publication status: | Published |
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| Publication version: | Version of Record |
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| Year of publishing: | 2026 |
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| Number of pages: | str. 717-725 |
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| Numbering: | Vol. 58 |
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| PID: | 20.500.12556/DiRROS-29215  |
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| UDC: | 575 |
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| ISSN on article: | 1546-1718 |
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| DOI: | 10.1038/s41588-026-02535-9 |
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| COBISS.SI-ID: | 274741251 |
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| Note: | Nasl. z nasl. zaslona;
Opis vira z dne 9. 4. 2026;
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| Publication date in DiRROS: | 24.04.2026 |
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| Views: | 30 |
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| Downloads: | 15 |
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