Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

Abstract

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E–09 and 4.10E–18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study

“…A hypergeometric test found signi cant overlap (p = 5.699e-07) between the 500 gene network generated by NAGA and the 500 gene network generated by network propagation analysis in our previous study 23 . There were 33 genes that were common to both networks.…”

“…In this study, we attempted to replicate our previous results which were from an independent sample 23 . We used network methods via NAGA to reprioritize GWAS results from the ConLiGen study on lithium response and used STRING to test three a priori network hypotheses: KEGG focal adhesion, ECM-receptor interaction and PI3K-Akt signaling.…”

“…We rst tested the three a priori pathways that were signi cant in our previous study, which had examined an independent sample 23 . Using the STRING analysis function, the top 500 reprioritized gene list generated by NAGA was found to be signi cantly enriched in both the KEGG hsa04510 focal adhesion pathway (p = 1.74e-06) and KEGG hsa04151 PI3K-Akt signaling pathway (p = 1.90e-07).…”

Transcriptomic and epigenomic consequences of heterozygous loss of function mutations inAKAP11, the first large-effect shared risk gene for bipolar disorder and schizophrenia

“…We found that heterozygous knockout of AKAP11 led to upregulation of pathways such as actin-binding, calcium ion binding, SH3 domain binding, lipid binding, and PDZ domain binding, which include genes involved in cell adhesion, motility, ECM interactions, or cytoskeletal integrity--pathways that have been previously suggested to be associated with lithium response 96,97 . Moreover, we found that the upregulated genes that were linked to increased intronic enhancer activity were primarily enriched in similar pathways suggesting that intronic enhancer activity through HATs and/or HDACs, plays a role, at least in part, in such dysregulations.…”

Alterations of plasma neuron-derived exosomal microRNAs in patients with bipolar disorder

“…underlined the direct rami cations of focal adhesion dysregulation on axon guidance and neuronal circuits. This intricate relationship might very well lay the foundation for BD's mechanistic intricacies and its amelioration upon lithium intervention [39]. Further emphasizing the role of neuronal pathways, the observed aberrancies in axon guidance hint at a potential fallout from dysregulated miRNAs present in neuron-derived exosomes from patients with BD.…”