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In healthy individuals, hippocampal volume was measured using MRI. Analyses were performed stratified by rs7587026 type. To study the functional consequences of increased <jats:italic>SCN1A<\/jats:italic> expression, we generated, using transposon-mediated bacterial artificial chromosome transgenesis, a zebrafish line expressing exogenous <jats:italic>scn1a<\/jats:italic>, and performed EEG analysis on larval optic tecta at 4\u00a0day post-fertilization. Finally, we used an in vitro promoter analysis to study whether the genetic motif containing rs7587026 influences promoter activity. Hippocampal <jats:italic>SCN1A<\/jats:italic> expression differed by rs7587026 genotype (Kruskal\u2013Wallis test <jats:italic>P<\/jats:italic>\u2009=\u20090.004). Individuals homozygous for the minor allele showed significantly increased expression compared to those homozygous for the major allele (Dunn\u2019s test <jats:italic>P<\/jats:italic>\u2009=\u20090.003), and to heterozygotes (Dunn\u2019s test <jats:italic>P<\/jats:italic>\u2009=\u20090.035). No statistically significant differences in hippocampal neuronal cell loss were observed between the three genotypes. Among 597 healthy participants, individuals homozygous for the minor allele at rs7587026 displayed significantly reduced mean hippocampal volume compared to major allele homozygotes (Cohen\u2019s <jats:italic>D<\/jats:italic>\u2009=\u2009\u2212\u00a00.28, <jats:italic>P<\/jats:italic>\u2009=\u20090.02), and to heterozygotes (Cohen\u2019s <jats:italic>D<\/jats:italic>\u2009=\u2009\u2212\u00a00.36, <jats:italic>P<\/jats:italic>\u2009=\u20090.009). Compared to wild type, <jats:italic>scn1lab<\/jats:italic>-overexpressing zebrafish larvae exhibited more frequent spontaneous seizures [one-way ANOVA <jats:italic>F<\/jats:italic>(4,54)\u2009=\u20096.95 (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001)]. The number of EEG discharges correlated with the level of <jats:italic>scn1lab<\/jats:italic> overexpression [one-way ANOVA <jats:italic>F<\/jats:italic>(4,15)\u2009=\u200910.75 (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001]. Finally, we showed that a 50\u00a0bp promoter motif containing rs7587026 exerts a strong regulatory role on <jats:italic>SCN1A<\/jats:italic> expression, though we could not directly link this to rs7587026 itself. Our results develop the mechanistic link between rs7587026 and mesial temporal lobe epilepsy with hippocampal sclerosis and a history of febrile seizures. Furthermore, we propose that quantitative precision may be important when increasing <jats:italic>SCN1A<\/jats:italic> expression in current strategies aiming to treat seizures in conditions involving <jats:italic>SCN1A<\/jats:italic> haploinsufficiency, such as Dravet syndrome.<\/jats:p>","DOI":"10.1007\/s00401-022-02429-0","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T12:06:05Z","timestamp":1652357165000},"page":"107-127","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["SCN1A overexpression, associated with a genomic region marked by a risk variant for a common epilepsy, raises seizure susceptibility"],"prefix":"10.1007","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8456-0029","authenticated-orcid":false,"given":"Katri","family":"Silvennoinen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kinga","family":"Gawel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Despina","family":"Tsortouktzidis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julika","family":"Pitsch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saud","family":"Alhusaini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen M. 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His work was conducted while affiliated at the Department of Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, and the Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California. PMT also received research grant funding from Biogen, Inc., for research unrelated to this manuscript. The remaining authors report no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study of <i>SCN1A<\/i> expression and neuronal loss in hippocampal specimens from individuals with MTLEHS was approved by the Ethical Commission of University Hospital Bonn (222\/16). The replication study of neuronal loss in hippocampal specimens from individuals with MTLEHS was approved by UK National Research Ethics (17\/SC\/0573). The QTIM study was approved by the Human Research Ethics Committees of the University of Queensland and the QIMR Berghofer Medical Research Institute.\u00a0The in vitro promoter analysis was approved by\u00a0the Ethical Commission of University Hospital Bonn (196\/17).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and\/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All experiments involving zebrafish were performed in compliance with the European Community Council Directive of November 2010 for Care and Use of Laboratory Animals (Directive 2010\/63\/EU), and the ARRIVE guidelines. The Norwegian Food Safety Authority via its experimental animal administration\u2019s supervisory and application system approved all animal experimentation (FOTS ID 15469 and 23935).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Research involves human or animals participants"}},{"value":"Informed consent was obtained from all individual participants included in the study.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}}]}}