{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T15:14:47Z","timestamp":1791213287689,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2022,7,10]],"date-time":"2022-07-10T00:00:00Z","timestamp":1657411200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["Intramural Research Program (project numbers: 1ZIA"],"award-info":[{"award-number":["Intramural Research Program (project numbers: 1ZIA"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014530","name":"Genome Center, University of California, Davis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014530","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Loss\u2010of\u2010function mutations in <jats:italic>GRN<\/jats:italic> are a cause of familial frontotemporal dementia, and common variants within the gene have been associated with an increased risk of developing Alzheimer's disease and Parkinson's disease. Although TDP\u201043\u2010positive inclusions are characteristic of <jats:italic>GRN\u2010<\/jats:italic>related neurodegeneration, Lewy body copathology has also been observed in many <jats:italic>GRN<\/jats:italic> mutation carriers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>The objective of this study was to assess a Lewy body dementia (LBD) case\u2013control cohort for pathogenic variants in <jats:italic>GRN<\/jats:italic> and to test whether there is an enrichment of damaging mutations among patients with LBD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed whole\u2010genome sequencing data generated for 2591 European\u2010ancestry LBD cases and 4032 neurologically healthy control subjects to identify disease\u2010causing mutations in <jats:italic>GRN.<\/jats:italic><\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified six heterozygous exonic <jats:italic>GRN<\/jats:italic> mutations in seven study participants (cases: n\u00a0=\u00a06; control subjects: n\u00a0=\u00a01). Each variant was predicted to be pathogenic or likely pathogenic. We found significant enrichment of <jats:italic>GRN<\/jats:italic> loss\u2010of\u2010function mutations in patients with LBD compared with control subjects (Optimized Sequence Kernel Association Test <jats:italic>P<\/jats:italic>\u00a0=\u20090.0162). Immunohistochemistry in three definite LBD cases demonstrated Lewy body pathology and TDP\u201043\u2010positive neuronal inclusions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings suggest that deleterious <jats:italic>GRN<\/jats:italic> mutations are a rare cause of familial LBD. \u00a9 2022 International Parkinson Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.29144","type":"journal-article","created":{"date-parts":[[2022,7,10]],"date-time":"2022-07-10T08:53:55Z","timestamp":1657443235000},"page":"1943-1948","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["<scp>GRN<\/scp> Mutations Are Associated with Lewy Body Dementia"],"prefix":"10.1002","volume":"37","author":[{"given":"Paolo","family":"Reho","sequence":"first","affiliation":[{"name":"Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8868-9700","authenticated-orcid":false,"given":"Shunsuke","family":"Koga","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Mayo Clinic  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