{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T08:03:40Z","timestamp":1767945820207,"version":"3.49.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:00:00Z","timestamp":1767916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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 utilized REGENIE software and LOFTEE-defined HC PTVs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We 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 (\n                      <jats:italic>BLVRB<\/jats:italic>\n                      ,\n                      <jats:italic>KLHL32<\/jats:italic>\n                      ,\n                      <jats:italic>RIMS2<\/jats:italic>\n                      ,\n                      <jats:italic>DYDC2<\/jats:italic>\n                      ,\n                      <jats:italic>DCBLD1<\/jats:italic>\n                      ,\n                      <jats:italic>ANXA4<\/jats:italic>\n                      ,\n                      <jats:italic>COMP<\/jats:italic>\n                      ,\n                      <jats:italic>TRIM42<\/jats:italic>\n                      ,\n                      <jats:italic>ANO4<\/jats:italic>\n                      ,\n                      <jats:italic>NFX1<\/jats:italic>\n                      ,\n                      <jats:italic>CFAP206<\/jats:italic>\n                      ,\n                      <jats:italic>CKAP2L<\/jats:italic>\n                      , and\n                      <jats:italic>ANGPTL4<\/jats:italic>\n                      ) 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\u2019 expression in brain regions, with the hypothalamus showing the highest specificity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2025.1735522","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T06:38:06Z","timestamp":1767940686000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring rare coding variants in UK biobank: preliminary associations with motor neuron disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhen","family":"Hu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing-jin","family":"Wan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qin-qin","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"eadf4428","DOI":"10.1126\/scitranslmed.adf4428","article-title":"Prospective study design and data analysis in UK biobank","volume":"16","author":"Allen","year":"2024","journal-title":"Sci. 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