Novel integrative genomic tool for interrogating lithium response in bipolar disorder

Abstract

We developed a novel integrative genomic tool called GRANITE (Genetic Regulatory Analysis of Networks Investigational Tool Environment) that can effectively analyze large complex data sets to generate interactive networks. GRANITE is an open-source tool and invaluable resource for a variety of genomic fields. Although our analysis is confined to static expression data, GRANITE has the capability of evaluating time-course data and generating interactive networks that may shed light on acute versus chronic treatment, as well as evaluating dose response and providing insight into mechanisms that underlie therapeutic versus sub-therapeutic doses or toxic doses. As a proof-of-concept study, we investigated lithium (Li) response in bipolar disorder (BD). BD is a severe mood disorder marked by cycles of mania and depression. Li is one of the most commonly prescribed and decidedly effective treatments for many patients (responders), although its mode of action is not yet fully understood, nor is it effective in every patient (non-responders). In an in vitro study, we compared vehicle versus chronic Li treatment in patient-derived lymphoblastoid cells (LCLs) (derived from either responders or non-responders) using both microRNA (miRNA) and messenger RNA gene expression profiling. We present both Li responder and non-responder network visualizations created by our GRANITE analysis in BD. We identified by network visualization that the Let-7 family is consistently downregulated by Li in both groups where this miRNA family has been implicated in neurodegeneration, cell survival and synaptic development. We discuss the potential of this analysis for investigating treatment response and even providing clinicians with a tool for predicting treatment response in their patients, as well as for providing the industry with a tool for identifying network nodes as targets for novel drug discovery.

Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder

“…Accordingly, different, more homogeneous phenotypes have been identified within patients regarding their likelihood of showing an adequate response to lithium treatment (responders vs. nonresponders) (Geoffroy et al, 2017; Oedegaard et al, 2016; Scott et al, 2017; Sportiche et al, 2016), and the genetic basis of lithium responsiveness has been consistently shown by several studies (Alda, 2015; Alda et al, 2005; Grof et al, 2009; Grof et al, 2002; Hou et al, 2016). This is also supported by in vitro studies performed with LCLs, in which lithium has been shown to exert specific effects based on the donor’s treatment responsiveness (Hunsberger et al, 2015; Milanesi et al, 2015; Squassina et al, 2013). In fact, cellular features of induced pluripotent stem cell-derived neurons derived from B-lymphocytes and fibroblasts have also been recently shown to discriminate between lithium responders and non-responders (Mertens et al, 2015; Stern et al, 2017), suggesting that a further investigation of our findings in regards to lithium responsiveness is now warranted.…”

“…Among cellular models, lymphoblastoid cell lines (LCLs) derived from the transformation of patients’ lymphocytes represent a valid and useful experimental tool (Breen et al, 2016; Hunsberger et al, 2015; Kittel-Schneider et al, 2015; Sugawara et al, 2010). Accordingly, alterations in the expression of specific genes in LCLs might help understand which genes might be linked to lithium treatment, thus shedding light into its mechanisms of action and clarifying the beneficial effects of lithium in patients.…”

Diagnostic and therapeutic potential of microRNAs in neuropsychiatric disorders: Past, present, and future

“…Different studies have suggested that changes in miRNA expression can be used to monitor response to mood stabilizers. For instance, Hunsberger et al showed that lithium treatment down-regulates let-7 miRNA family expression in lymphoblastoid cells in BD lithium responders (Hunsberger et al, 2015). In another example, Rong et al reported that plasma miRNA-134 levels in drug-free patients with BD mania are significantly lower compared to control subjects.…”

TLX—Its Emerging Role for Neurogenesis in Health and Disease

“…Profiling of miR expression in SZ and BP post-mortem brains as well as genome-wide association studies (GWAS) have indicated miRs in the aetiologies of these disorders [80]. TLX is targeted by several miRs, among which miR137 displayed the highest degrees of gene variation in a GWAS study of SZ and BP [81]. Administration of lithium and other mood stabilisers seems to downregulate the miR let-7 family in both treatment responders and non-responders [81].…”

“…TLX is targeted by several miRs, among which miR137 displayed the highest degrees of gene variation in a GWAS study of SZ and BP [81]. Administration of lithium and other mood stabilisers seems to downregulate the miR let-7 family in both treatment responders and non-responders [81]. The let-7 family has also been suggested to affect synaptic development [82], and its expression in the brain can be modulated by sleep deprivation [83].…”