| Title: |
Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder |
| Authors: |
Mühleisen, 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 |
| Source: |
urn:ISSN:0165-0327 ; urn:ISSN:1573-2517 ; Journal of Affective Disorders, 228, 20-25 |
| Publisher Information: |
Elsevier |
| Publication Year: |
2018 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
32 Biomedical and Clinical Sciences; 42 Health Sciences; 52 Psychology; Human Genome; Bipolar Disorder; Brain Disorders; Mental Health; Serious Mental Illness; Neurosciences; Genetics; Mental Illness; 2.1 Biological and endogenous factors; Algorithms; Brain; Female; GRB2 Adaptor Protein; Gene Expression; Genes; erbB-2; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Phenotype; Polymorphism; Single Nucleotide; RNA; Erb-b2 Receptor Tyrosine Kinases; Signal Transduction; GRB2 events in ERBB2 signaling |
| Description: |
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 FDR = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (P FDR = 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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
https://hdl.handle.net/1959.4/unsworks_49676; https://doi.org/10.1016/j.jad.2017.11.068 |
| DOI: |
10.1016/j.jad.2017.11.068 |
| Availability: |
https://hdl.handle.net/1959.4/unsworks_49676; https://unsworks.unsw.edu.au/bitstreams/4bfc82b1-a667-4881-9a9c-144ea89d129e/download; https://doi.org/10.1016/j.jad.2017.11.068 |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC-BY-NC-ND ; https://creativecommons.org/licenses/by-nc-nd/4.0/ ; free_to_read |
| Accession Number: |
edsbas.ECAFC916 |
| Database: |
BASE |