Pantovic-Stefanovic, Maja (35085268700)Maja (35085268700)Pantovic-StefanovicKaranovic, Jelena (56055635600)Jelena (56055635600)KaranovicJurisic, Vladimir (6603015144)Vladimir (6603015144)JurisicDunjic-Kostic, Bojana (36760738400)Bojana (36760738400)Dunjic-KosticNesic, Milica (59357410100)Milica (59357410100)NesicDodic, Sara (57934136000)Sara (57934136000)DodicGostiljac, Marta (59358792200)Marta (59358792200)GostiljacPuric, Marija (59358597900)Marija (59358597900)PuricSavic Pavicevic, Dusanka (57212301497)Dusanka (57212301497)Savic PavicevicIvkovic, Maja (6603636580)Maja (6603636580)Ivkovic2025-06-122025-06-122024https://doi.org/10.1186/s12888-024-06207-yhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85208162266&doi=10.1186%2fs12888-024-06207-y&partnerID=40&md5=2c825fc363c32b7de4d75f8b7dbee439https://remedy.med.bg.ac.rs/handle/123456789/774Background: Although repeatedly confirmed, the molecular nature of gene-environment (GxE) interactions has rarely been investigated in the clinical context of mood disorders. This study assesses the relationship between HTR2A genetic variants and the modulatory effect of inflammation in a collective cohort of patients with major depressive disorder (MDD) and bipolar disorder (BD), as a unified group with two distinct phenotypes. Methods: The study included 138 patients with acute mood episodes (BD = 83; MDD = 55). HTR2A rs6313 and rs6314 genotyping was performed while measuring platelet-derived indicators of inflammation (platelet count (PLT), mean platelet volume (MPV), plateletcrit, and platelet distribution width) and the MPV/PLT ratio. Results: The HTR2A rs6313 variant is a significant predictor of the polarity phenotype in mood disorders, with the MPV/PLT ratio moderating this relationship, but only under low-inflammatory conditions. In more pronounced inflammatory states, genetic influences lose their predictive role. Conclusions: To our knowledge, this is the first study to investigate the complex interplay between platelet-derived indicators of inflammation and HTR2A variants in the context of mood disorders. Without pro-inflammatory conditions, mood disorders seem to be more genetically determined. Under pro-inflammatory conditions, phenotypic presentation is less dependent on genetic factors. GxE interactions in mood disorders are multifaceted, context-dependent and relevant for assessing their clinical presentation and course. © The Author(s) 2024.Bipolar disorderGene-environment interactionsHTR2A rs6313Mood disordersUnipolar depression