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Health","doi-asserted-by":"publisher","award":["R01 NS065070"],"award-info":[{"award-number":["R01 NS065070"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50 NS062684"],"award-info":[{"award-number":["P50 NS062684"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS096740"],"award-info":[{"award-number":["R01NS096740"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      The aim of this study was to search for genes\/variants that modify the effect of\n                      <jats:italic>LRRK2<\/jats:italic>\n                      mutations in terms of penetrance and age\u2010at\u2010onset of Parkinson's disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed the first genomewide association study of penetrance and age\u2010at\u2010onset of Parkinson's disease in\n                      <jats:italic>LRRK2<\/jats:italic>\n                      mutation carriers (776 cases and 1,103 non\u2010cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age\u2010at\u2010onset of\n                      <jats:italic>LRRK2<\/jats:italic>\n                      mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age\u2010at\u2010onset in\n                      <jats:italic>LRRK2<\/jats:italic>\n                      mutation carriers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A variant located in the intronic region of\n                      <jats:italic>CORO1C<\/jats:italic>\n                      on chromosome 12 (rs77395454;\n                      <jats:italic>p<\/jats:italic>\n                      value\u00a0=\u00a02.5E\u201008, beta\u00a0=\u00a01.27, SE\u00a0=\u00a00.23, risk allele: C) met genomewide significance for the penetrance model. Co\u2010immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant:\n                      <jats:italic>p<\/jats:italic>\n                      value\u00a0=\u00a01.1E\u201007; age\u2010at\u2010onset top variant:\n                      <jats:italic>p<\/jats:italic>\n                      value\u00a0=\u00a09.3E\u201007). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age\u2010at\u2010onset.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      This study suggests that variants within or near\n                      <jats:italic>CORO1C<\/jats:italic>\n                      may modify the penetrance of\n                      <jats:italic>LRRK2<\/jats:italic>\n                      mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of\n                      <jats:italic>LRRK2<\/jats:italic>\n                      mutations. ANN NEUROL 2021;90:82\u201394\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.26094","type":"journal-article","created":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T01:21:56Z","timestamp":1620004916000},"page":"76-88","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Genomewide Association Studies of\n                    <scp>\n                      <i>LRRK2<\/i>\n                    <\/scp>\n                    Modifiers of Parkinson's Disease"],"prefix":"10.1002","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7803-580X","authenticated-orcid":false,"given":"Dongbing","family":"Lai","sequence":"first","affiliation":[{"name":"Department of Medical and Molecular Genetics Indiana University School of Medicine  Indianapolis IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Babak","family":"Alipanahi","sequence":"additional","affiliation":[{"name":"23andMe, Inc.  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Macdonald Department of Human Genetics University of Miami, Miller School of Medicine  Miami FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Berg","sequence":"additional","affiliation":[{"name":"Department of Neurology Christian\u2010Albrechts\u2010University of Kiel  Kiel Germany"},{"name":"Department of Neurodegenerative Diseases Hertie Institute for Clinical Brain Research, University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Bressman","sequence":"additional","affiliation":[{"name":"Department of Neurology Icahn School of Medicine at Mount Sinai  New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Brice","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Institut du Cerveau et de la Moelle \u00e9pini\u00e8re (ICM), AP\u2010HP, Inserm, CNRS, University Hospital Piti\u00e9\u2010Salp\u00eatri\u00e8re  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7515-8596","authenticated-orcid":false,"given":"Kathrin","family":"Brockman","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases Hertie Institute for Clinical Brain Research, University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE)  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorraine","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology Columbia University  New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Cookson","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics National Institute of Aging, National Institute of Health  Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayantan","family":"Das","sequence":"additional","affiliation":[{"name":"23andMe, Inc.  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Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital  Toronto Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. William","family":"Langston","sequence":"additional","affiliation":[{"name":"Departments of Neurology, Neuroscience, and Pathology Stanford University School of Medicine  Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne","family":"Latourelle","sequence":"additional","affiliation":[{"name":"GNS Healthcare  Cambridge MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Lynch","sequence":"additional","affiliation":[{"name":"Dublin Neurological Institute at the Mater Misericordiae University Hospital, Conway Institute of Biomolecular and Biomedical Research, University College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Marder","sequence":"additional","affiliation":[{"name":"Department of Neurology and Psychiatry Taub Institute and Sergievsky Center, Columbia University Vagelos College of Physicians and Surgeons  New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connie","family":"Marras","sequence":"additional","affiliation":[{"name":"The Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital  Toronto Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eden R.","family":"Martin","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Department of Human Genetics University of Miami, Miller School of Medicine  Miami FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cory Y.","family":"McLean","sequence":"additional","affiliation":[{"name":"23andMe, Inc.  Sunnyvale CA"},{"name":"Google LLC  Cambridge MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Mejia\u2010Santana","sequence":"additional","affiliation":[{"name":"Gertrude H. 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