{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T12:43:16Z","timestamp":1789735396244,"version":"4.0.1"},"reference-count":60,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2020,6,18]],"date-time":"2020-06-18T00:00:00Z","timestamp":1592438400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009477","name":"Lottery Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009477","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["16229"],"award-info":[{"award-number":["16229"]}],"id":[{"id":"10.13039\/100000864","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":[[2020,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p><jats:italic>GBA<\/jats:italic> mutations are numerically the most significant genetic risk factor for Parkinson's disease (PD), yet these mutations have low penetrance, suggesting additional mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>The objective of this study was to determine if the penetrance of <jats:italic>GBA<\/jats:italic> in PD can be explained by regulatory effects on <jats:italic>GBA<\/jats:italic> and modifier genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Genetic variants associated with the regulation of <jats:italic>GBA<\/jats:italic> were identified by screening 128 common single nucleotide polymorphisms (SNPs) in the <jats:italic>GBA<\/jats:italic> locus for spatial <jats:italic>cis\u2010<\/jats:italic>expression quantitative trail locus (supported by chromatin interactions).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified common noncoding SNPs within <jats:italic>GBA<\/jats:italic> that (1) regulate GBA expression in peripheral tissues, some of which display \u03b1\u2010synuclein pathology and (2) coregulate potential modifier genes in the central nervous system and\/or peripheral tissues. Haplotypes based on 3 of these SNPs delay disease onset by 5\u2009years. In addition, SNPs on 6 separate chromosomes coregulate <jats:italic>GBA<\/jats:italic> expression specifically in either the substantia nigra or cortex, and their combined effect potentially modulates motor and cognitive symptoms, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This work provides a new perspective on the haplotype\u2010specific effects of <jats:italic>GBA<\/jats:italic> and the genetic etiology of PD, expanding the role of <jats:italic>GBA<\/jats:italic> from the gene encoding the \u03b2\u2010glucocerebrosidase (GCase) to that of a central regulator and modifier of PD onset, with <jats:italic>GBA<\/jats:italic> expression itself subject to distant regulation. Some idiopathic patients might possess insufficient <jats:italic>GBA<\/jats:italic>\u2010encoded GCase activity in the substantia nigra as the result of distant regulatory variants and therefore might benefit from <jats:italic>GBA<\/jats:italic>\u2010targeting therapeutics. The SNPs\u2019 regulatory impacts provide a plausible explanation for the variable phenotypes also observed in <jats:italic>GBA<\/jats:italic>\u2010centric Gaucher's disease and dementia with Lewy bodies. \u00a9 2020 The Authors. <jats:italic>Movement Disorders<\/jats:italic> published by Wiley Periodicals, LLC on behalf of International Parkinson and Movement Disorder Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.28144","type":"journal-article","created":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T02:17:11Z","timestamp":1592533031000},"page":"1346-1356","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Common Variants Coregulate Expression of <scp><i>GBA<\/i><\/scp> and Modifier Genes to Delay Parkinson's Disease 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