{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:21:19Z","timestamp":1792131679740,"version":"4.4.0"},"reference-count":48,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,8,29]],"date-time":"2015-08-29T00:00:00Z","timestamp":1440806400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Ontario Mental Health Foundation"},{"name":"A Brain & Behavior Research Foundation NARSAD grant"},{"name":"The NIH National Institute of Mental Health","award":["R01MH099167,"],"award-info":[{"award-number":["R01MH099167,"]}]},{"name":"A Centre for Addiction and Mental Health Fellowship"},{"DOI":"10.13039\/501100000243","name":"The W. Garfield Weston Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000243","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000038","name":"The Natural Sciences and Engineering Research Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009408","name":"Brain Canada","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100009408","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000024","name":"The Canadian Institutes of Health Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Edmond J. Safra Philanthropic Foundation"},{"DOI":"10.13039\/100000864","name":"The Michael J. Fox Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The National Parkinson Foundation"},{"DOI":"10.13039\/501100000263","name":"Parkinson Society Canada","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000263","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Tourette Syndrome Association"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Serum urate levels have been associated with risk for and progression of Parkinson's disease (PD). Urate\u2010related compounds are therapeutic candidates in neuroprotective efforts to slow PD progression. A urate\u2010elevating agent is currently under investigation as a potential disease\u2010modifying strategy in people with PD. However, PD is a heterogeneous disorder, and genetic variation may explain divergence in disease severity and progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a genome\u2010wide association study to identify gene variant \u00d7 serum urate interaction effects on the striatal <jats:sup>123<\/jats:sup>I\u2010ioflupane (DaTscan) binding ratio measured using single photon emission computed tomography in patients with possible PD from the Parkinson's Progression Markers Initiative (PPMI, n = 360). Follow\u2010up analyses were conducted to assess gene variant \u00d7 serum urate interaction effects on magnetic resonance imaging\u2013derived regional brain volumes and clinical status. We then attempted to replicate our primary analysis in patients who entered the Parkinson Research Examination of CEP\u20101347 Trial (PRECEPT) with a clinical diagnosis of PD (n = 349).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Rs1109303 (T&gt;G) variant within the <jats:italic>INPP5K<\/jats:italic> gene on chromosome 17p13.3 demonstrated a genome\u2010wide significant interaction with serum urate level to predict striatal dopamine transporter density among all PPMI participants (n = 359) with possible PD (<jats:italic>p<\/jats:italic> = 2.01 \u00d7 10<jats:sup>\u22128<\/jats:sup>; after excluding participants with SWEDD [scan without evidence of dopaminergic deficit]: <jats:italic>p<\/jats:italic> = 1.12 \u00d7 10<jats:sup>\u22129<\/jats:sup>; n = 316). Independent of striatal dopamine transporter density, similar effects on brain atrophy, bradykinesia, anxiety, and depression were observed. No effect was present in the PRECEPT sample at baseline; however, in non\u2010SWEDD PD participants in PRECEPT (n = 309), we observed a significant longitudinal genotype \u00d7 serum urate interaction effect, consistent in direction with the PPMI sample, on progression of striatal dopamine transporter density over the 22\u2010month follow\u2010up.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Genetic profile combined with serum urate level can be used to predict disease severity and potential disease progression in patients with PD. These results may be relevant to therapeutic efforts targeting the urate pathway. Ann Neurol 2015;78:Ann Neurol 2015;78:679\u2013696<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.24504","type":"journal-article","created":{"date-parts":[[2015,8,18]],"date-time":"2015-08-18T23:41:18Z","timestamp":1439941278000},"page":"731-741","source":"Crossref","is-referenced-by-count":10,"title":["Genome\u2010wide variant by serum urate interaction in Parkinson's disease"],"prefix":"10.1002","volume":"78","author":[{"given":"Arash","family":"Nazeri","sequence":"first","affiliation":[{"name":"Kimel Family Translational Imaging\u2013Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Institute Centre for Addiction and Mental Health Toronto Ontario Canada"},{"name":"Department of Psychiatry University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Roostaei","sequence":"additional","affiliation":[{"name":"Kimel Family Translational Imaging\u2013Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Institute Centre for Addiction and Mental Health Toronto Ontario Canada"},{"name":"Department of Psychiatry University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shokufeh","family":"Sadaghiani","sequence":"additional","affiliation":[{"name":"Kimel Family Translational Imaging\u2013Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Institute Centre for Addiction and Mental Health Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Mallar","family":"Chakravarty","sequence":"additional","affiliation":[{"name":"Cerebral Imaging Centre Douglas Institute Montreal Quebec Canada"},{"name":"Departments of Psychiatry and Biomedical Engineering McGill University Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirley","family":"Eberly","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Computational Biology University of Rochester Medical Center Rochester NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony E.","family":"Lang","sequence":"additional","affiliation":[{"name":"Morton and Gloria Shulman Movement Disorders Clinic and Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital University Health Network, Division of Neurology Toronto Ontario Canada"},{"name":"Division of Neurology, Department of Medicine University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aristotle N.","family":"Voineskos","sequence":"additional","affiliation":[{"name":"Kimel Family Translational Imaging\u2013Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Institute Centre for Addiction and Mental Health Toronto Ontario Canada"},{"name":"Department of Psychiatry University of Toronto Toronto Ontario Canada"},{"name":"Institute of Medical Science University of Toronto Toronto Ontario Canada"},{"name":"Underserved Populations Program Centre for Addiction and Mental Health Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,8,29]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.78.11.6858"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-130230"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwm127"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2009.247"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.2008.65.6.nct70003"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24281"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0037331"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1217296110"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12038"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2013.5528"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2011.08.002"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.2337\/db10-0916"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0b013e3283550c0d"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1993"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2011.09.005"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts606"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts610"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0019416"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1006\/nimg.2000.0582"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2007.07.007"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.1058"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2011.09.015"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2008.03.061"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000277648.63931.c0"},{"key":"e_1_2_8_27_1","article-title":"What do patients with scans without evidence of dopaminergic deficit (SWEDD) have? 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