{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T17:27:40Z","timestamp":1791912460456,"version":"4.3.4"},"reference-count":75,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To examine the associations of\n                      <jats:italic>LRRK2<\/jats:italic>\n                      p.G2019S,\n                      <jats:italic>GBA1<\/jats:italic>\n                      p.N409S, polygenic risk scores (PRS), and\n                      <jats:italic>APOE<\/jats:italic>\n                      E4 on PD penetrance, risk, and symptoms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted a US\u2010based observational case\u2013control study using data from the 23andMe Inc. and Fox Insight Genetic Substudy (FIGS) databases. The total cohort included 7,586,842 participants (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200935,163 PD); 8791\n                      <jats:italic>LRRK2<\/jats:italic>\n                      p.G2019S carriers (565 with PD), 37,427\n                      <jats:italic>GBA1<\/jats:italic>\n                      p.N409S carriers (524 with PD), 244 dual\n                      <jats:italic>LRRK2<\/jats:italic>\n                      \/GBA1 carriers (37 with PD), and 7.5 million noncarriers (34,037 with PD). PRS was calculated from the most recently published European genome\u2010wide association study. Survival models estimated the cumulative incidence of PD. Logistic regressions estimated the relative odds of reporting motor and non\u2010motor symptoms according to genetic exposure.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      By the age of 80\u2009years, the cumulative incidence of PD was 30% for dual carriers, 24% for\n                      <jats:italic>LRRK2<\/jats:italic>\n                      p.G2019S carriers, 4% for\n                      <jats:italic>GBA1<\/jats:italic>\n                      p.N409S carriers, and 2% for noncarriers. Higher PRS was associated with increased penetrance of the variants and earlier time to PD diagnosis.\n                      <jats:italic>GBA1<\/jats:italic>\n                      p.N409S PD was associated with the highest burden of non\u2010motor symptoms, including REM sleep behavior disorder and cognitive\/memory deficits, and\n                      <jats:italic>LRRK2<\/jats:italic>\n                      p.G2019S with the lowest.\n                      <jats:italic>APOE<\/jats:italic>\n                      E4 dosage was associated with greater odds of reporting hallucinations and cognitive impairment in addition to carrier status.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Our findings support the use of genetic screening to enrich candidate selection for neuroprotective trials and better define outcome measures based on genetics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70176","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T07:06:21Z","timestamp":1757487981000},"page":"2482-2494","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Genetic Modifiers of Parkinson's Disease: A Case\u2013Control Study"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5340-3872","authenticated-orcid":false,"given":"Matthew J.","family":"Kmiecik","sequence":"first","affiliation":[{"name":"23andMe, Inc.  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