TY - JOUR
T1 - An integrative genomic study implicates the postsynaptic density in the pathogenesis of bipolar disorder
AU - Akula, Nirmala
AU - Wendland, Jens R.
AU - Choi, Kwang H.
AU - McMahon, Francis J.
N1 - Funding Information:
We thank Drs Michael B Knable, E Fuller Torrey, Maree J Webster, Serge Weis, and Robert H Yolken at The Stanley Medical Research Institute for sharing brain tissue. We also thank Drs Barbara K Lipska and Joel E Kleinman at NIMH-IRP for providing us RNA from three control brains. Data analysis was performed on the Biowulf high-performance computing platform at the NIH. This study was funded by the Intramural Research Program of the NIMH (ZIAMH002810).
Publisher Copyright:
© 2016 American College of Neuropsychopharmacology. All rights reserved.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - Genome-wide association studies (GWAS) have identified several common variants associated with bipolar disorder (BD), but the biological meaning of these findings remains unclear. Integrative genomics - the integration of GWAS signals with gene expression data - may illuminate genes and gene networks that have key roles in the pathogenesis of BD. We applied weighted gene co-expression network analysis (WGCNA), which exploits patterns of co-expression among genes, to brain transcriptome data obtained by sequencing of poly-A RNA derived from postmortem dorsolateral prefrontal cortex from people with BD, along with age- and sex-matched controls. WGCNA identified 33 gene modules. Many of the modules corresponded closely to those previously reported in human cortex. Three modules were associated with BD, enriched for genes differentially expressed in BD, and also enriched for signals in prior GWAS of BD. Functional analysis of genes within these modules revealed significant enrichment of several functionally related sets of genes, especially those involved in the postsynaptic density (PSD). These results provide convergent support for the hypothesis that dysregulation of genes involved in the PSD is a key factor in the pathogenesis of BD. If replicated in larger samples, these findings could point toward new therapeutic targets for BD.
AB - Genome-wide association studies (GWAS) have identified several common variants associated with bipolar disorder (BD), but the biological meaning of these findings remains unclear. Integrative genomics - the integration of GWAS signals with gene expression data - may illuminate genes and gene networks that have key roles in the pathogenesis of BD. We applied weighted gene co-expression network analysis (WGCNA), which exploits patterns of co-expression among genes, to brain transcriptome data obtained by sequencing of poly-A RNA derived from postmortem dorsolateral prefrontal cortex from people with BD, along with age- and sex-matched controls. WGCNA identified 33 gene modules. Many of the modules corresponded closely to those previously reported in human cortex. Three modules were associated with BD, enriched for genes differentially expressed in BD, and also enriched for signals in prior GWAS of BD. Functional analysis of genes within these modules revealed significant enrichment of several functionally related sets of genes, especially those involved in the postsynaptic density (PSD). These results provide convergent support for the hypothesis that dysregulation of genes involved in the PSD is a key factor in the pathogenesis of BD. If replicated in larger samples, these findings could point toward new therapeutic targets for BD.
UR - http://www.scopus.com/inward/record.url?scp=84953898329&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84953898329&partnerID=8YFLogxK
U2 - 10.1038/npp.2015.218
DO - 10.1038/npp.2015.218
M3 - Article
C2 - 26211730
AN - SCOPUS:84953898329
SN - 0893-133X
VL - 41
SP - 886
EP - 895
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 3
ER -