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The two corticoid receptors encoded by the genes <jats:italic>NR3C1<\/jats:italic> and <jats:italic>NR3C2<\/jats:italic> are the main players in regulating the physiological response to cortisol. This biological system has been linked to neurocognitive processes and memory, yet the mechanisms remain largely unclear. In two independent general population studies (SHIP, total sample size\u2009&gt;\u20095500), we aim to diseantangle the effects of genetic variation, gene expression and cortisol on verbal memory and memory associated brain volume. Especially for <jats:italic>NR3C1<\/jats:italic> results exhibited a consistent pattern of direct an interactive effects. All three biological layers, genetic variation (rs56149945), gene expression for <jats:italic>NR3C1<\/jats:italic> and cortisol levels, were directly associated with verbal memory. Interactions between these components showed significant effects on verbal memory as well as hippocampal volume. For <jats:italic>NR3C2<\/jats:italic> such a complex association pattern could not be observed. Our analyses revealed that different components of the stress response system are acting together on different aspects of cognition. Complex phenotypes, such as cognition and memory function are regulated by a complex interplay between different genetic and epigenetic features. We promote the glucocorticoid receptor <jats:italic>NR3C1<\/jats:italic> as a main target to focus in the context of verbal memory and provided a mechanistic concept of the interaction between various biological layers spanning <jats:italic>NR3C1<\/jats:italic> function and its effects on memory. Especially the <jats:italic>NR3C1<\/jats:italic> transcript seemed to be a key element in this complex system.<\/jats:p>","DOI":"10.1007\/s00406-022-01420-w","type":"journal-article","created":{"date-parts":[[2022,5,17]],"date-time":"2022-05-17T12:15:35Z","timestamp":1652789735000},"page":"1505-1516","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The interplay between genetic variation and gene expression of the glucocorticoid receptor gene NR3C1 and blood cortisol levels on verbal memory and hippocampal volumes"],"prefix":"10.1007","volume":"272","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1757-7768","authenticated-orcid":false,"given":"Sandra","family":"Van der Auwera","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johanna","family":"Klinger-K\u00f6nig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Wittfeld","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Terock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anke","family":"Hannemann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin","family":"B\u00fclow","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Nauck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uwe","family":"V\u00f6lker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry","family":"V\u00f6lzke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans J\u00f6rgen","family":"Grabe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,5,17]]},"reference":[{"key":"1420_CR1","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1016\/j.neuron.2022.02.020","volume":"110","author":"L Schwabe","year":"2022","unstructured":"Schwabe L, Hermans EJ, Jo\u00ebls M, Roozendaal B (2022) Mechanisms of memory under stress. 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The interpretation of the data was not influenced by any funding. HJG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. All other authors declare that no conflicts of interest exist.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}