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Fox Foundation for Parkinson\u2019s Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006775","name":"GE | GE Healthcare","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006775","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["npj Parkinsons Dis."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The genetic basis of levodopa-induced-dyskinesia (LiD) is poorly understood, and there have been few well-powered genome-wide studies. We performed a genome-wide survival meta-analyses to study the effect of genetic variation on the development of LiD in five separate longitudinal cohorts, and meta-analysed the results. We included 2784 PD patients, of whom 14.6% developed LiD. We found female sex (HR\u2009=\u20091.35, SE\u2009=\u20090.11,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.007) and younger age at onset (HR\u2009=\u20091.8, SE\u2009=\u20090.14,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20092\u2009\u00d7\u200910\n                    <jats:sup>\u22125<\/jats:sup>\n                    ) increased the probability of developing LiD. We identified three genetic loci significantly associated with time-to-LiD onset.\n                    <jats:bold>rs72673189<\/jats:bold>\n                    on chromosome 1 (HR\u2009=\u20092.77, SE\u2009=\u20090.18,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20091.53\u2009\u00d7\u200910\n                    <jats:sup>\u22128<\/jats:sup>\n                    ) located at the LRP8 locus,\n                    <jats:bold>rs189093213 on<\/jats:bold>\n                    chromosome 4 (HR\u2009=\u20093.06, SE\u2009=\u20090.19,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20092.81\u2009\u00d7\u200910\n                    <jats:sup>\u22129<\/jats:sup>\n                    ) in the non-coding RNA\n                    <jats:italic>LINC02353<\/jats:italic>\n                    locus, and\n                    <jats:bold>rs180924818<\/jats:bold>\n                    on chromosome 16 (HR\u2009=\u20093.13, SE\u2009=\u20090.20,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20096.27\u2009\u00d7\u200910\n                    <jats:sup>\u22129<\/jats:sup>\n                    ) in the\n                    <jats:italic>XYLT1<\/jats:italic>\n                    locus. Based on a functional annotation analysis on chromosome 1, we determined that changes in DNAJB4 gene expression, close to LRP8, are an additional potential cause of increased susceptibility to LiD. Baseline anxiety status was significantly associated with LiD (OR\u2009=\u20091.14, SE\u2009=\u20090.03,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20097.4\u2009\u00d7\u200910\n                    <jats:sup>\u22125<\/jats:sup>\n                    ). Finally, we performed a candidate variant analysis of previously reported loci, and found that genetic variability in\n                    <jats:italic>ANKK1<\/jats:italic>\n                    (\n                    <jats:italic>rs1800497<\/jats:italic>\n                    , HR\u2009=\u20091.27, SE\u2009=\u20090.09,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20098.89\u2009\u00d7\u200910\n                    <jats:sup>\u22123<\/jats:sup>\n                    ) and\n                    <jats:italic>BDNF<\/jats:italic>\n                    (\n                    <jats:italic>rs6265<\/jats:italic>\n                    , HR\u2009=\u20091.21, SE\u2009=\u20090.10,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20094.95\u2009\u00d7\u200910\n                    <jats:sup>\u22122<\/jats:sup>\n                    ) loci were significantly associated with time to LiD in our large meta-analysis.\n                  <\/jats:p>","DOI":"10.1038\/s41531-023-00573-2","type":"journal-article","created":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T14:02:31Z","timestamp":1693490551000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Genetic meta-analysis of levodopa induced dyskinesia in Parkinson\u2019s disease"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6191-1703","authenticated-orcid":false,"given":"Alejandro","family":"Martinez-Carrasco","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8117-742X","authenticated-orcid":false,"given":"Raquel","family":"Real","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3419-0354","authenticated-orcid":false,"given":"Michael","family":"Lawton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotaka","family":"Iwaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5835-669X","authenticated-orcid":false,"given":"Manuela M. 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Research Grants from Parkinson\u2019s UK, Cure Parkinson\u2019s Trust, PSP Association, CBD Solutions, Drake Foundation, Medical Research Council (MRC), Michael J. Fox Foundation. Dr Morris is a co-applicant on a patent application related to C9ORF72 - Method for diagnosing a neurodegenerative disease (PCT\/GB2012\/052140). D.G.G. has received grants from Michael\u2019s Movers, the Neurosciences Foundation, and Parkinson\u2019s UK, and honoraria from AbbVie, BIAL Pharma, Britannia Pharmaceuticals, GE Healthcare, and consultancy fees from Acorda Therapeutics and the Glasgow Memory Clinic. M.T.M.H. received funding\/grant support from Parkinson\u2019s UK, Oxford NIHR BRC, University of Oxford, CPT, Lab10X, NIHR, Michael J. Fox Foundation, H2020 European Union, GE Healthcare and the PSP Association. She also received payment for Advisory Board attendance\/consultancy for Biogen, Roche, Sanofi, CuraSen Therapeutics, Evidera, Manus Neurodynamica, Lundbeck. Y.B.-S. has received grant funding from the MRC, NIHR, Parkinson\u2019s UK, NIH, and ESRC. C.C receives salary from University Hospitals Plymouth NHS Trust and National Institute of Health and Care Research. She has received advisory, consulting or lecture fees from AbbVie, Bial, Scient, Orkyn, Abidetex, UCB, Pfizer, EverPharma, Lundbeck, Global Kinetics, Kyowa Kirin, Britannia and Medscape, and research funding from Parkinson\u2019s UK, Edmond J Safra Foundation, National Institute of Health and Care Research and Cure Parkinson\u2019s. J.H. is supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer\u2019s Society, and Alzheimer\u2019s Research UK. He is also supported by the MRC, Wellcome Trust, Dolby Family Fund, National Institute for Health Research University, College London Hospitals Biomedical Research Centre. All other authors report no competing interests. M.A.L. received fees for advising on a secondary analysis of an RCT sponsored by North Bristol NHS trust that studied off-state Dyskinesia.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"128"}}