{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T09:05:26Z","timestamp":1780909526119,"version":"3.54.1"},"reference-count":61,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC2703101"],"award-info":[{"award-number":["2022YFC2703101"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Brain and Behavior"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Autophagy dysregulation has been implicated in the toxic protein aggregates of amyotrophic lateral sclerosis (ALS). However, the causal relationship between impaired autophagy and ALS remains ambiguous, necessitating further elucidation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This Mendelian randomization (MR) study employs a two\u2010sample design, utilizing genetic instruments to proxy autophagy dysregulation as the exposure and ALS as the outcome. It incorporates summary statistics of ALS (27,205 cases, 110,881 controls), along with data on DNA methylation, RNA splicing, gene expression, and protein abundance quantitative trait loci (QTLs) in both blood and brain tissues (mQTL, sQTL, eQTL, and pQTL, respectively) sourced from European cohorts.\n                      <jats:italic>Cis<\/jats:italic>\n                      \u2010variants situated proximal to or within the 604 autophagy\u2010related genes, exhibiting robust associations with molecular alterations in autophagy, are employed as instrumental variables. Their causal links with ALS are assessed via summary\u2010data\u2010based MR (SMR) analyses, followed by Bayesian colocalization, sensitivity analyses, brain cell\u2010specific MR analyses, protein\u2013protein interaction (PPI), and druggable analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Consistent evidence supported the causal effects of two lysosome genes (\n                      <jats:italic>FNBP1<\/jats:italic>\n                      and\n                      <jats:italic>IDUA<\/jats:italic>\n                      ), one autophagy core gene (\n                      <jats:italic>C9orf72<\/jats:italic>\n                      ), and one mitophagy gene (\n                      <jats:italic>USP35<\/jats:italic>\n                      ) on ALS risk. Specifically, brain\n                      <jats:italic>FNBP1<\/jats:italic>\n                      splicing level (OR = 1.18,\n                      <jats:italic>p<\/jats:italic>\n                      = 3.38E\u20105) and blood\n                      <jats:italic>USP35<\/jats:italic>\n                      expression level (OR = 1.17,\n                      <jats:italic>p<\/jats:italic>\n                      = 5.94E\u20105) were positively associated with higher ALS risk. In contrast, we found strong causal evidence of brain\n                      <jats:italic>IDUA<\/jats:italic>\n                      methylation level (OR = 0.96,\n                      <jats:italic>p<\/jats:italic>\n                      = 8.36E\u20106) and blood\n                      <jats:italic>C9orf72<\/jats:italic>\n                      methylation level (OR = 0.55,\n                      <jats:italic>p<\/jats:italic>\n                      = 7.59E\u201012) with lower ALS risk. Cell\u2010type\u2010specific MR analyses, PPI, and druggable analyses further nominated the key brain cell type (astrocytes), potential interaction with known causative genes (\n                      <jats:italic>SQSTM1<\/jats:italic>\n                      and\n                      <jats:italic>PFN1<\/jats:italic>\n                      ), and promising druggability for\n                      <jats:italic>FNBP1<\/jats:italic>\n                      in ALS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This multi\u2010omics MR study identified causal associations between the regulation of four autophagy\u2010related genes and ALS risk, shedding light on autophagy\u2010mediated mechanisms and offering early evidence of novel therapeutic targets for ALS.<\/jats:p>\n                  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