{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:16:36Z","timestamp":1792790196711,"version":"4.5.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2023,1,1]],"date-time":"2023-01-01T00:00:00Z","timestamp":1672531200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>In a genome-wide association study of intracranial aneurysms (IA), enrichment was found between genes associated with IA and genes encoding targets of effective anti-epileptic drugs. Our aim was to assess if this pleiotropy is driven by shared disease mechanisms that could potentially highlight a treatment strategy for IA.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Using 2-sample inverse-variance weighted Mendelian randomization and genetic colocalization analyses we assessed: (1) if epilepsy liability in general affects IA risk, and (2) whether changes in gene- and protein-expression levels of anti-epileptic drug targets in blood and arterial tissue may causally affect IA risk.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We found no overall effect of epilepsy liability on IA. Expression of 21 genes and 13 proteins corresponding to anti-epileptic drug targets supported a causal effect (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.05) on IA risk. Of those genes and proteins, genetic variants affecting\n              <jats:italic>CNNM2<\/jats:italic>\n              levels showed strong evidence for colocalization with IA risk (posterior probability&gt;70%). Higher\n              <jats:italic>CNNM2<\/jats:italic>\n              levels in arterial tissue were associated with increased IA risk (odds ratio, 3.02; [95% CI, 2.32\u20133.94];\n              <jats:italic>P<\/jats:italic>\n              =3.39\u00d710\n              <jats:sup>\u2212<\/jats:sup>\n              <jats:sup>16<\/jats:sup>\n              ). CNNM2 expression was best proxied by rs11191580. The magnitude of the effect of this variant was greater than would be expected if systemic blood pressure was the sole IA-causing mechanism in this locus.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              <jats:italic>CNNM2<\/jats:italic>\n              is a driver of the pleiotropy between IA and anti-epileptic drug targets. Administration of the anti-epileptic drugs phenytoin, valproic acid, or carbamazepine may be expected to decrease\n              <jats:italic>CNNM2<\/jats:italic>\n              levels and therefore subsequently decrease IA risk.\n              <jats:italic>CNNM2<\/jats:italic>\n              is therefore an important target to investigate further for its role in the pathogenesis of IA.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.122.040598","type":"journal-article","created":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T09:00:20Z","timestamp":1666861220000},"page":"208-216","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":37,"title":["Anti-Epileptic Drug Target Perturbation and Intracranial Aneurysm Risk: Mendelian Randomization and Colocalization Study"],"prefix":"10.1161","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7887-9014","authenticated-orcid":true,"given":"Mark K.","family":"Bakker","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, the Netherlands (M.K.B., T.v.S., Y.M.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9119-9286","authenticated-orcid":true,"given":"Tijmen","family":"van Straten","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, the Netherlands (M.K.B., T.v.S., Y.M.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0555-4622","authenticated-orcid":true,"given":"Michael","family":"Chong","sequence":"additional","affiliation":[{"name":"Population Health Research Institute; Thrombosis and Atherosclerosis Research Institute; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario (M.C., G.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6795-4760","authenticated-orcid":true,"given":"Guillaume","family":"Par\u00e9","sequence":"additional","affiliation":[{"name":"Population Health Research Institute; Thrombosis and Atherosclerosis Research Institute; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario (M.C., G.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7312-7078","authenticated-orcid":true,"given":"Dipender","family":"Gill","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, United Kingdom (D.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5396-2989","authenticated-orcid":true,"given":"Ynte M.","family":"Ruigrok","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, the Netherlands (M.K.B., T.v.S., Y.M.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(11)70109-0"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(09)70126-7"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.108.531277"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1159\/000353642"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1212\/CPJ.0b013e31828d9f6b"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.117.020342"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.114.006096"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-21603-7"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00725-7"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.563"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.934"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.308765"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07524-z"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00913-z"},{"key":"e_1_3_3_16_2","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nature24277","article-title":"Genetic effects on gene expression across human tissues.","volume":"550","author":"GTEx C","year":"2017","unstructured":"GTEx, C. 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