Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder.

TitleGene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder.
Publication TypeJournal Article
Year of Publication2018
AuthorsMühleisen TW, Reinbold CS, Forstner AJ, Abramova LI, Alda M, Babadjanova G, Bauer M, Brennan P, Chuchalin A, Cruceanu C, Czerski PM, Degenhardt F, Fischer SB, Fullerton JM, Gordon SD, Grigoroiu-Serbanescu M, Grof P, Hauser J, Hautzinger M, Herms S, Hoffmann P, Kammerer-Ciernioch J, Khusnutdinova E, Kogevinas M, Krasnov V, Lacour A, Laprise C, Leber M, Lissowska J, Lucae S, Maaser A, Maier W, Martin NG, Mattheisen M, Mayoral F, McKay JD, Medland SE, Mitchell PB, Moebus S, Montgomery GW, Müller-Myhsok B, Oruc L, Pantelejeva G, Pfennig A, Pojskic L, Polonikov A, Reif A, Rivas F, Rouleau GA, Schenk LM, Schofield PR, Schwarz M, Streit F, Strohmaier J, Szeszenia-Dabrowska N, Tiganov AS, Treutlein J, Turecki G, Vedder H, Witt SH, Schulze TG, Rietschel M, Nöthen MM, Cichon S
JournalJ Affect Disord
Date Published2018 03 01

BACKGROUND: Bipolar 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.METHODS: 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.RESULTS: 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 (P = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (P = 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.LIMITATIONS: 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.CONCLUSIONS: 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.

Alternate JournalJ Affect Disord
PubMed ID29197740
Grant ListMOP-13506 / / Canadian Institutes of Health Research / International