{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T01:03:16Z","timestamp":1760576596828,"version":"build-2065373602"},"reference-count":68,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":45,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Ischemic stroke (IS) is a leading cause of death in elderly people. Previous studies exploring the association between intraocular pressure (IOP), glaucoma, and IS have provided inconsistent results. Here, we aimed to clarify this causal relationship, as a better understanding may reveal novel therapeutic targets and preventive strategies. We performed a bidirectional Mendelian randomization (MR) study to explore the causal relationship between IOP, glaucoma, and IS. Complementary studies such as MR-Egger regression, MR-PRESSO, and MRlap were conducted to assess the robustness of the causal associations. Next, the single nucleotide polymorphisms (SNPs) selected as instrumental variables for IOP and primary open-angle glaucoma (POAG) were mapped to relevant genes by the novel combined SNP-to-gene (cS2G) method. Genes showing significant causal effects on IS were further subjected to gene ontology (GO), pathway, and colocalization (COLOC) analyses. We also performed single SNP Mendelian randomization study to identify the SNPs of IOP and glaucoma with significant causal influence on IS risk, which were then introduced to the cytogenetic investigation. The MR results supported that the elevated IOP and POAG may contribute to increased IS risk, but not vice versa. By using the cS2G approach, we identified 31 and 3 genes potentially playing key roles in the IOP- and POAG-induced IS risk, respectively. GO and pathway analyses indicated the olfactory pathway as a crucial mechanism in the IOP-associated risk. COLOC further strengthened the causal implications of genes CDKN2A and CDKN2B-AS1 between POAG and IS. This work provides evidence supporting the causal implications between IOP, POAG, and IS, and highlights putative pathway and genes for managing both conditions. Moreover, our study could serve as a novel paradigm for exploring the in-depth causal relationships in other diseases.<\/jats:p>","DOI":"10.1093\/bib\/bbaf546","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T20:23:13Z","timestamp":1760559793000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrative genetic analysis reveals new relationships between intraocular pressure, glaucoma, and ischemic stroke risk: a study based on combined SNP-to-gene, Mendelian randomization and pathway investigations"],"prefix":"10.1093","volume":"26","author":[{"given":"Qi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology, The Affiliated Taizhou People\u2019s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University , Taizhou, Jiangsu 225300 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Di","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Children\u2019s Hospital of Fudan University , Shanghai 201102 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5501-6657","authenticated-orcid":false,"given":"Zenan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Affiliated Taizhou People\u2019s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University , Taizhou, Jiangsu 225300 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junhong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai Eye Disease Prevention & Treatment Center\/Shanghai Eye Hospital, School of Medicine, Tongji University , Shanghai 200041 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