Muhleisen, Thomas WReinbold, Celine SForstner, Andreas JAbramova, Lilia IAlda, MartinBabadjanova, GuljaBauer, MichaelBrennan, PaulChuchalin, AlexanderCruceanu, CristianaCzerski, Piotr MDegenhardt, FranziskaFischer, Sascha BFullerton, Janice MGordon, Scott DGrigoroiu-Serbanescu, MariaGrof, PaulHauser, JoannaHautzinger, MartinHerms, StefanHoffmann, PerKammerer-Ciernioch, JuttaKhusnutdinova, ElzaKogevinas, ManolisKrasnov, ValeryLacour, AndreLaprise, CatherineLeber, MarkusLissowska, JolantaLucae, SusanneMaaser, AnnaMaier, WolfgangMartin, Nicholas GMattheisen, ManuelMayoral, FerminMcKay, James DMedland, Sarah EMitchell, Philip BMoebus, SusanneMontgomery, Grant WMuller-Myhsok, BertramOruc, LilijanaPantelejeva, GalinaPfennig, AndreaPojskic, LejlaPolonikov, AlexeyReif, AndreasRivas, FabioRouleau, Guy ASchenk, Lorena MSchofield, Peter RSchwarz, MarkusStreit, FabianStrohmaier, JanaSzeszenia-Dabrowska, NeonilaTiganov, Alexander STreutlein, JensTurecki, GustavoVedder, HelmutWitt, Stephanie HSchulze, Thomas GRietschel, MarcellaNothen, Markus MCichon, Sven2023-01-252023-01-252018-01-04Mühleisen TW, Reinbold CS, Forstner AJ, Abramova LI, Alda M, Babadjanova G, et al. Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder. J Affect Disord. 2018 Mar 1;228:20-25http://hdl.handle.net/10668/11867Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci. We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan. Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (PFDR = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (PFDR = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system. Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients. Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD.enBipolar disorderGRB2 events in ERBB2 signalingNCAM signaling for neurite out-growthNeurodevelopmental disorderPathway analysisAlgorithmsBipolar DisorderBrainFemaleGRB2 Adaptor ProteinGene ExpressionGenes, erbB-2Genetic Predisposition to DiseaseGenome-Wide Association StudyHumansMalePhenotypePolymorphism, Single NucleotideRNAReceptor, ErbB-2Signal Transductionresearch article29197740Restricted AccessExpresión GénicaLongevidadDesarrollo FetalEstudio de Asociación del Genoma CompletoMoléculas de Adhesión de Célula NerviosaTrastorno Bipolar10.1016/j.jad.2017.11.0681573-2517