{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:14:56Z","timestamp":1785428096461,"version":"3.56.0"},"reference-count":47,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013317","name":"Shanxi Science and Technology Department","doi-asserted-by":"publisher","award":["202503021211130"],"award-info":[{"award-number":["202503021211130"]}],"id":[{"id":"10.13039\/501100013317","id-type":"DOI","asserted-by":"publisher"}]},{"award":["202503021211130"],"award-info":[{"award-number":["202503021211130"]}],"id":[{"id":"https:\/\/ror.org\/05vp4an32","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Restless legs syndrome (RLS) is a common sensorimotor disorder with limited treatment options and incompletely understood pathophysiology. Genome-wide association studies have identified numerous risk loci, but translating these findings into causal genes and therapeutic targets remains challenging. We performed a proteome-wide association study (PWAS) integrating RLS genome-wide association study (GWAS) data from FinnGen with two brain pQTL datasets (ROSMAP and Banner). We validated the identified proteins using TWAS, SMR, and colocalization analyses using brain pQTL and eQTL datasets. To further investigate peripheral protein associations, we performed SMR using plasma pQTL data from the UK Biobank Pharma Proteomics Project (UKB-PPP). We also conducted a phenome-wide association study (PheWAS) to screen for potential off-target effects of the prioritized genes, followed by drug prediction using DSigDB and molecular docking. PWAS identified GLO1, along with GRWD1 and MAP2K5, as significantly associated with RLS. GLO1 was identified by brain-based SMR (p = 0.0001), colocalization (PP.H4 = 0.96), TWAS (p = 0.048), and was confirmed by plasma-based SMR (p = 3.16 \u00d7 10\u22129) as the only protein associated with RLS. PheWAS analysis, without associations for 783 non-RLS phenotypes, confirmed the specificity of GLO1. Among 27 predicted GLO1-targeting compounds, Gambierol had the strongest binding affinity (\u22128.3 kcal\/mol). This proteogenomic study identifies GLO1 as a prioritized causal gene and promising drug target for RLS, combining brain and plasma data to provide new insights into pathogenesis and candidate drug development.<\/jats:p>","DOI":"10.3390\/ijms27104446","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T14:40:31Z","timestamp":1779115231000},"page":"4446","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integration of Brain Proteomes and Genome-Wide Association Data Identifies GLO1 as a Candidate Causal Gene and Therapeutic Target for Restless Legs Syndrome"],"prefix":"10.3390","volume":"27","author":[{"given":"Lingyu","family":"Zhang","sequence":"first","affiliation":[{"name":"Shanxi Key Laboratory of Human Disease and Animal Models, Experimental Animal Center of Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Forensic Pathology, Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruochen","family":"Du","sequence":"additional","affiliation":[{"name":"Shanxi Key Laboratory of Human Disease and Animal Models, Experimental Animal Center of Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0590-1724","authenticated-orcid":false,"given":"Yuxiang","family":"Liang","sequence":"additional","affiliation":[{"name":"Shanxi Key Laboratory of Human Disease and Animal Models, Experimental Animal Center of Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.sleep.2014.03.025","article-title":"Restless legs syndrome\/Willis-Ekbom disease diagnostic criteria: Updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria\u2013history, rationale, description, and significance","volume":"15","author":"Allen","year":"2014","journal-title":"Sleep Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/s41572-021-00311-z","article-title":"Restless legs syndrome","volume":"7","author":"Manconi","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1016\/S1474-4422(18)30311-9","article-title":"Comorbidities, treatment, and pathophysiology in restless legs syndrome","volume":"17","author":"Trenkwalder","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.smrv.2011.05.002","article-title":"Epidemiology of restless legs syndrome: A synthesis of the literature","volume":"16","author":"Ohayon","year":"2012","journal-title":"Sleep Med. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.sleep.2018.09.019","article-title":"Suicidal thought and behavior in individuals with restless legs syndrome","volume":"54","author":"Para","year":"2019","journal-title":"Sleep Med."},{"key":"ref_6","first-page":"137","article-title":"Treatment of restless legs syndrome and periodic limb movement disorder: An American Academy of Sleep Medicine clinical practice guideline","volume":"21","author":"Winkelman","year":"2025","journal-title":"J. Clin. Sleep Med. JCSM Off. Publ. Am. Acad. Sleep Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"532","DOI":"10.17992\/lbl.2025.12.868","article-title":"New recommedations in the treatment of restless legs syndrome-dopaminergic drugs on the way out","volume":"111","author":"Sveinsson","year":"2025","journal-title":"Laeknabladid"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1212\/WNL.0b013e318294b3f6","article-title":"Thalamic glutamate\/glutamine in restless legs syndrome: Increased and related to disturbed sleep","volume":"80","author":"Allen","year":"2013","journal-title":"Neurology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.sleep.2016.06.003","article-title":"Connectome and molecular pharmacological differences in the dopaminergic system in restless legs syndrome (RLS): Plastic changes and neuroadaptations that may contribute to augmentation","volume":"31","author":"Earley","year":"2017","journal-title":"Sleep Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.sleep.2018.02.002","article-title":"Treatment of restless legs syndrome\/Willis-Ekbom disease with the non-selective ENT1\/ENT2 inhibitor dipyridamole: Testing the adenosine hypothesis","volume":"45","author":"Guitart","year":"2018","journal-title":"Sleep Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/s42003-020-01430-1","article-title":"Large genome-wide association study identifies three novel risk variants for restless legs syndrome","volume":"3","author":"Didriksen","year":"2020","journal-title":"Commun. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1038\/s41588-024-01763-1","article-title":"Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction","volume":"56","author":"Schormair","year":"2024","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1002\/ana.27040","article-title":"Genomic Analysis Identifies Risk Factors in Restless Legs Syndrome","volume":"96","author":"Chia","year":"2024","journal-title":"Ann. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1038\/s41593-021-00832-6","article-title":"Brain proteome-wide association study implicates novel proteins in depression pathogenesis","volume":"24","author":"Wingo","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/ng.3506","article-title":"Integrative approaches for large-scale transcriptome-wide association studies","volume":"48","author":"Gusev","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/s13195-025-01774-y","article-title":"Proteome-wide association studies using summary pQTL data of brain, CSF, and plasma identify 30 risk genes of Alzheimer\u2019s disease dementia","volume":"17","author":"Hu","year":"2025","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wang, Y., Zhang, S., Gong, W., Liu, X., Mo, Q., Shen, L., Zhao, Y., Wang, S., and Yuan, Z. (2024). Multi-Omics Integration Analysis Pinpoint Proteins Influencing Brain Structure and Function: Toward Drug Targets and Neuroimaging Biomarkers for Neuropsychiatric Disorders. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25179223"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1111\/neup.12189","article-title":"Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program","volume":"35","author":"Beach","year":"2015","journal-title":"Neuropathol. Off. J. Jpn. Soc. Neuropathol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Qian, R., Zhao, X., Lyu, D., Xu, Q., Yuan, K., Luo, X., Wang, W., Wang, Y., Liu, Y., and Cheng, Y. (2024). Identification of Causal Genes and Potential Drug Targets for Restless Legs Syndrome: A Comprehensive Mendelian Randomization Study. Pharmaceuticals, 17.","DOI":"10.3390\/ph17121626"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"j1182","DOI":"10.1126\/science.adj1182","article-title":"Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program","volume":"385","author":"Verma","year":"2024","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1016\/j.toxicon.2008.01.004","article-title":"Gambierol, a toxin produced by the dinoflagellate Gambierdiscus toxicus, is a potent blocker of voltage-gated potassium channels","volume":"51","author":"Cuypers","year":"2008","journal-title":"Toxicon Off. J. Int. Soc. Toxinology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9896","DOI":"10.1073\/pnas.0812471106","article-title":"A polyether biotoxin binding site on the lipid-exposed face of the pore domain of Kv channels revealed by the marine toxin gambierol","volume":"106","author":"Kopljar","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.bbrc.2007.07.009","article-title":"TRPV1 as a key determinant in ciguatera and neurotoxic shellfish poisoning","volume":"361","author":"Cuypers","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5898","DOI":"10.1093\/nar\/gkv509","article-title":"Cdt1-binding protein GRWD1 is a novel histone-binding protein that facilitates MCM loading through its influence on chromatin architecture","volume":"43","author":"Sugimoto","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Huang, Y., Wang, P., Morales, R., Luo, Q., and Ma, J. (2021). Map2k5-Deficient Mice Manifest Phenotypes and Pathological Changes of Dopamine Deficiency in the Central Nervous System. Front. Aging Neurosci., 13.","DOI":"10.3389\/fnagi.2021.651638"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Morgenstern, J., Campos Campos, M., Nawroth, P., and Fleming, T. (2020). The Glyoxalase System-New Insights into an Ancient Metabolism. Antioxidants, 9.","DOI":"10.3390\/antiox9100939"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1016\/j.jds.2025.04.022","article-title":"2-O-methylmagnolol mitigates the generation of reactive oxidative stress and inflammaging in human gingival epithelial cells and fibroblasts with advanced glycation end products stimulation","volume":"20","author":"Huang","year":"2025","journal-title":"J. Dent. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Va\u0161kov\u00e1, J., Kov\u00e1\u010dov\u00e1, G., Pudelsk\u00fd, J., Palen\u010d\u00e1r, D., and Mi\u010dkov\u00e1, H. (2025). Methylglyoxal Formation-Metabolic Routes and Consequences. Antioxidants, 14.","DOI":"10.3390\/antiox14020212"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1042\/CS20140683","article-title":"The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases","volume":"128","author":"Maessen","year":"2015","journal-title":"Clin. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.expneurol.2014.06.023","article-title":"Low brain iron effects and reversibility on striatal dopamine dynamics","volume":"261","author":"Unger","year":"2014","journal-title":"Exp. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/bs.apha.2019.02.003","article-title":"Non-dopaminergic vs. dopaminergic treatment options in restless legs syndrome","volume":"84","author":"Wanner","year":"2019","journal-title":"Adv. Pharmacol."},{"key":"ref_32","first-page":"1","article-title":"Guidelines for the first-line treatment of restless legs syndrome\/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: A combined task force of the IRLSSG, EURLSSG, and the RLS-foundation","volume":"21","author":"Silber","year":"2016","journal-title":"Sleep Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S440","DOI":"10.1002\/mds.21607","article-title":"The role of iron in restless legs syndrome","volume":"22","author":"Allen","year":"2007","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.sleep.2011.11.012","article-title":"Assessment of nitric oxide, advanced oxidation protein products, malondialdehyde, and thiol levels in patients with restless legs syndrome","volume":"13","author":"Baskol","year":"2012","journal-title":"Sleep Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/s41588-020-00773-z","article-title":"Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer\u2019s disease pathogenesis","volume":"53","author":"Wingo","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/s41593-020-0635-5","article-title":"Shared proteomic effects of cerebral atherosclerosis and Alzheimer\u2019s disease on the human brain","volume":"23","author":"Wingo","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1038\/nn.4399","article-title":"Gene expression elucidates functional impact of polygenic risk for schizophrenia","volume":"19","author":"Fromer","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/ng.3538","article-title":"Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets","volume":"48","author":"Zhu","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Giambartolomei, C., Vukcevic, D., Schadt, E.E., Franke, L., Hingorani, A.D., Wallace, C., and Plagnol, V. (2014). Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004383"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1038\/s41588-018-0184-y","article-title":"Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies","volume":"50","author":"Zhou","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3069","DOI":"10.1093\/bioinformatics\/btv313","article-title":"DSigDB: Drug signatures database for gene set analysis","volume":"31","author":"Yoo","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"W159","DOI":"10.1093\/nar\/gkac394","article-title":"CB-Dock2: Improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting","volume":"50","author":"Liu","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"D1388","DOI":"10.1093\/nar\/gkaa971","article-title":"PubChem in 2021: New data content and improved web interfaces","volume":"49","author":"Kim","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3755","DOI":"10.1093\/bioinformatics\/bty419","article-title":"NGL viewer: Web-based molecular graphics for large complexes","volume":"34","author":"Rose","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s10822-010-9352-6","article-title":"Ligand docking and binding site analysis with PyMOL and Autodock\/Vina","volume":"24","author":"Seeliger","year":"2010","journal-title":"J. Comput. Aided Mol. Des."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4446\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T04:29:54Z","timestamp":1779510594000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4446"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,15]]},"references-count":47,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27104446"],"URL":"https:\/\/doi.org\/10.3390\/ijms27104446","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,15]]}}}