乌得勒支大学Jan H. Veldink小组的研究发现大规模外显子组分析揭示了肌萎缩性侧索硬化症中新的罕见变异贡献。相关论文于2026年3月31日发表于国际顶尖学术期刊《自然—遗传学》杂志上。

为了确定这些罕见的变异，该课题组研究人员协调并分析了来自22个队列的外显子组数据，共17919名ALS患者和200703名对照组，跨越发现和复制阶段。罕见变异分析发现了几个新的风险基因，复制证实与YKT6相关，并支持HTR3C、GBGT1和KNTC1。课题组人员还对ARPP21、DNAJC7和CFAP410等先前证据有限的基因进行了强有力的独立验证。

值得注意的是，在ARPP21中，该研究组发现了一种新的高效变异（p.P747L），并证实p.P563L是一种与ALS相关的变异，导致侵袭性疾病本身。除了新发现之外，他们的分析在很大程度上概括了ALS的已知遗传结构，在超过20%的病例中确定了风险变异，并支持累积寡基因风险模型。这些发现突出了新的翻译靶点，并表明罕见变异分析比常见变异全基因组关联研究捕获了更多的遗传风险。

研究人员表示，肌萎缩性侧索硬化症（ALS）是一种遗传性疾病，具有低至中等外显率的罕见变异被认为是遗传风险的主要因素。

附：英文原文

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

Author: Hop, Paul J., Kooyman, Maarten, Kenna, Brendan J., Zwamborn, Ramona A. J., van Eijk, Kristel R., Wang, Yan, van Dijk, Charlotte H., Bekema, Erwin, van Rheenen, Wouter, Beele, Paul, van Vugt, Joke J. F. A., Khleifat, Ahmad Al, Iacoangeli, Alfredo, Cooper-Knock, Johnathan, Smith, Bradley N., Topp, Simon, van der Kooi, Anneke J., Fominykh, Vera, Drory, Vivian, Lerner, Yossef, Shovman, Yehuda, Rowe, Dominic B., Williams, Kelly L., McLaughlin, Russell L., Hurt, Jessica, Huang, Yunfeng, Chen, Chia-Yen, Tsai, Ellen, Runz, Heiko, Aronica, Eleonora, Groen, Ewout J. N., van Es, Michael A., Pasterkamp, R. Jeroen, Farhan, Sali M. K., Garton, Fleur C., McRae, Allan F., McCombe, Pamela A., Henderson, Robert D., Fan, Dongsheng, lachtov, Lenka, Hyer, Helle, Nishimura, Agnes L., Cauchi, Ruben J., Brylev, Lev, Rogelj, Boris, Koritnik, Bla, Zidar, Janez, Salas, Teresa, Mora Pardina, Jesus S., Gotkine, Marc, Povedano, Monica, Corcia, Philippe, Vourch, Patrick, Couratier, Philippe, Weber, Markus, Kiernan, Matthew C., Pamphlett, Roger, Blair, Ian P., de Carvalho, Mamede, Baak, Nazli A., Ingre, Caroline, Andersen, Peter M., Zinman, Lorne, Rogaeva, Ekaterina, MacKenzie, Ian R., Dupre, Nicolas, Rouleau, Guy A., Traynor, Bryan J., Ticozzi, Nicola

Issue&Volume: 2026-03-31

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.

DOI: 10.1038/s41588-026-02535-9

Source: https://www.nature.com/articles/s41588-026-02535-9