{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T06:03:30Z","timestamp":1779775410982,"version":"3.53.1"},"reference-count":29,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T00:00:00Z","timestamp":1770681600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T00:00:00Z","timestamp":1770681600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Amyotrophic lateral sclerosis (ALS) shows sex differences in incidence and age of onset, yet the underlying biological mechanisms remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated sex\u2010specific genetic architecture in an Italian ALS cohort with whole\u2010genome sequencing (1,333 ALS cases, 755 controls). We performed a sex\u2010stratified burden analysis of rare variants in ALS\u2010associated genes and compared the proportions of male and female ALS patients carrying pathogenic or rare damaging variants. Key findings were replicated in the AnswerALS cohort (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009723). Gene\u2010specific sex ratios and familial history for\n                      <jats:italic>C9ORF72<\/jats:italic>\n                      ,\n                      <jats:italic>SOD1<\/jats:italic>\n                      , and\n                      <jats:italic>TARDBP<\/jats:italic>\n                      were examined in an expanded dataset of 2,301 Italian ALS patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Sex\u2010stratified burden testing revealed that rare variants in ALS genes were enriched in female cases versus controls (odds ratio [OR] 5.47, 95% confidence interval [CI] 1.60\u201334.29) but not in male cases. Female ALS patients more frequently carried rare damaging variants compared to males (23.2% vs 18.3%; OR 1.38, 95% CI 1.05\u20131.81), a finding that was replicated in the AnswerALS cohort (18.9% vs 12.4%; OR 1.58, 95% CI 1.10\u20132.26). Gene\u2010level analyses of\n                      <jats:italic>TARDBP<\/jats:italic>\n                      carriers revealed a male predominance (2.1:1), yet a higher rate of familial history among females (40.4% vs 24.5%; OR 2.13, 95% CI 1.03\u20134.39).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Females with ALS exhibited a higher overall burden of rare damaging variants, suggesting sex\u2010related differences in genetic liability. Gene\u2010level analyses indicate that the influence of sex varies across ALS genes, particularly\n                      <jats:italic>TARDBP<\/jats:italic>\n                      . These findings help explain epidemiological patterns and have implications for the identification of sex\u2010linked protective mechanisms. ANN NEUROL 2026;99:1536\u20131544\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78172","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T11:16:06Z","timestamp":1770722166000},"page":"1536-1544","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sex\u2010Specific Genetic Architecture of\n                    <scp>ALS<\/scp>\n                    : Evidence of a Female Protective Effect?"],"prefix":"10.1002","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6714-6897","authenticated-orcid":false,"given":"Maurizio","family":"Grassano","sequence":"first","affiliation":[{"name":"Rita Levi Montalcini Department of Neuroscience University of Turin  Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Palumbo","sequence":"additional","affiliation":[{"name":"Rita Levi Montalcini Department of 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