ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Parkinson’s Disease and Aging-related Movement Disorders
This article is part of the Research TopicFrom Genetic Risk to Targeted Treatment in Neurodegenerative DisordersView all articles
Exploring Rare Coding Variants in UK Biobank: Preliminary Associations with Motor Neuron Disease
Provisionally accepted
- 1Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital Department of Neurology, Shanghai, China
- 2Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
- 3Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
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Previous studies have illuminated a significant genetic component in motor neuron disease (MND) pathogenesis, with several causative genes identified. However, a substantial proportion of MND cases remain genetically unexplained, particularly regarding the comprehensive contribution of rare, high-impact variants across the exome. Leveraging whole-exome sequencing data from nearly half a million UK Biobank participants, we systematically investigated the association between high-confidence protein-truncating variants (HC PTVs) and MND risk in a Caucasian subset. Our large-scale gene-based association analysis, utilizing REGENIE software and LOFTEE-defined HC PTVs, identified significant preliminary associations between HC PTVs in 14 genes and an increased risk of MND. Notably, while NEK1 has been previously implicated in ALS, the remaining 13 genes (BLVRB, KLHL32, RIMS2, DYDC2, DCBLD1, ANXA4, COMP, TRIM42, ANO4, NFX1, CFAP206, CKAP2L, and ANGPTL4) show preliminary associations as novel candidate loci for the disease. Functional enrichment analyses further indicated that these genes are significantly involved in critical biological pathways, including collagen-containing extracellular matrix organization and ciliary function. Furthermore, tissue specificity analysis highlighted a strong enrichment of these genes' expression in brain regions, with the hypothalamus showing the highest specificity. These findings suggest a potential expansion of the known genetic landscape of MND, and highlight novel biological pathways implicated in its pathogenesis. This study underscores the power of large-scale population genetics in uncovering critical disease mechanisms and offers new avenues for mechanistic research and therapeutic development for MND, pending independent validation.
Keywords: Motor Neuron Disease, protein-truncating variants, rare variants, Risk facors, UK Biobank
Received: 30 Oct 2025; Accepted: 17 Dec 2025.
Copyright: © 2025 Hu, Wan, Yan, Fan and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yu Fan
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