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As one of the first findings being confirmed by genome-wide association studies for the phenotype of panic disorder and agoraphobia, allelic variation in a gene coding for the glycine receptor beta subunit (<jats:italic>GLRB<\/jats:italic>) has recently been associated with increased neural fear network activation and enhanced acoustic startle reflexes. On the basis of two independent healthy control samples, we here aimed to further explore the functional significance of the <jats:italic>GLRB<\/jats:italic> genotype (rs7688285) by employing an intermediate phenotype approach. We focused on the phenotype of defensive system reactivity across the levels of brain function, structure, and physiology. Converging evidence across both samples was found for increased neurofunctional activation in the (anterior) insular cortex in <jats:italic>GLRB<\/jats:italic> risk allele carriers and altered fear conditioning as a function of genotype. The robustness of <jats:italic>GLRB<\/jats:italic> effects is demonstrated by consistent findings across different experimental fear conditioning paradigms and recording sites. Altogether, findings provide translational evidence for glycine neurotransmission as a modulator of the brain\u2019s evolutionary old dynamic defensive system and provide further support for a strong, biologically plausible candidate intermediate phenotype of defensive reactivity. As such, glycine-dependent neurotransmission may open up new avenues for mechanistic research on the etiopathogenesis of fear and anxiety disorders.<\/jats:p>","DOI":"10.1038\/tp.2017.186","type":"journal-article","created":{"date-parts":[[2017,9,5]],"date-time":"2017-09-05T13:42:36Z","timestamp":1504618956000},"page":"e1227-e1227","update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Modulation of defensive reactivity by GLRB allelic variation: converging evidence from an intermediate phenotype approach"],"prefix":"10.1038","volume":"7","author":[{"given":"U","family":"Lueken","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Kuhn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B","family":"Straube","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T","family":"Kircher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H-U","family":"Wittchen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B","family":"Pfleiderer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V","family":"Arolt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Wittmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Str\u00f6hle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H","family":"Weber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Reif","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K","family":"Domschke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Deckert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T B","family":"Lonsdorf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,9,5]]},"reference":[{"key":"BFtp2017186_CR1","doi-asserted-by":"crossref","unstructured":"Deckert J, Weber H, Villmann C, Lonsdorf TB, Richter J, Andreatta M et al. 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H-UW has been member of advisory boards of several pharmaceutical companies. He received travel reimbursements and research grant support from Essex Pharma, Sanofi, Pfizer, Organon, Servier, Novartis, Lundbeck, Glaxo Smith Kline. VA is member of advisory boards and\/or gave presentations for the following companies: Astra-Zeneca, Janssen-Organon, Lilly, Lundbeck, Servier, Pfizer, and Wyeth. He also received research grants from Astra-Zeneca, Lundbeck, and Servier. He chaired the committee for the \u2018Wyeth Research Award Depression and Anxiety\u2019. AS received research funding from the German Federal Ministry of Education and Research, the European Commission (FP6) and Lundbeck, and speaker honoraria from Astra-Zeneca, Boehringer Ingelheim, Eli Lilly & Co, Lundbeck, Pfizer, Wyeth, and UCB. Educational grants were given by the Stifterverband f\u00fcr die Deutsche Wissenschaft, the Berlin Brandenburgische Akademie der Wissenschaften, the Boehringer Ingelheim Fonds and the Eli Lilly International Foundation. AR has received a research grant from Medice, and speaker\u2019s honoraria from Medice and neuraxpharm. The remaining authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}