Bipolar Disorder Study Finds Role for Gene Expression Changes Affecting Nerve Synapses

Researchers from Johns Hopkins School of Medicine examined gene expression changes in certain brain regions in people with bipolar disorder, as compared to neurotypical controls. Bipolar disorder affects about 7 million people in the US, is marked by episodes of mania and depression, and can be difficult to treat. 

In their transcriptomic study, the researchers uncovered nearly 1,000 differentially expressed genes. Many of these differentially expressed genes could be traced to two networks: one enriched for microglia-associated genes as well as immune- and inflammatory-related genes and a second enriched for synaptic-related pathways and a key gene involved in the organization of certain receptors at the synapse, as the researchers reported Monday in Nature Neuroscience. 

"This is the first deep dive into the molecular biology of the brain in people who died with bipolar disorder — studying actual genes, not urine, blood, or skin samples," senior author Thomas Hyde from Johns Hopkins and the Lieber Institute said in a statement. "If we can figure out the mechanisms behind [bipolar disorder], if we can figure out what's wrong in the brain, then we can begin to develop new targeted treatments of what has long been a mysterious condition." 

The researchers performed RNA sequencing on 511 brain tissue samples from 295 donors, 138 individuals with bipolar disorder and 157 controls. They focused their analysis on two brain regions, the amygdala and the subgenual anterior cingulate cortex, which are involved in regulating behavior, emotion, and memory and have been implicated in mood regulation and bipolar disorder. 

About 960 unique genes were differentially expressed between the groups, with most of the difference in expression being noted in the subgenual anterior cingulate cortex. Further, most of the affected genes were protein coding. 

Through a weighted gene coexpression network analysis, the researchers identified 20 gene modules. The top module associated with bipolar disorder encompassed genes that tended to be downregulated in the condition and included a number of microglia-specific genes as well as genes in immune- and inflammatory-related pathways, providing additional evidence for a role of microglia in bipolar disorder. 

Four of those genes, the researchers noted, have also been linked to Alzheimer's disease, which previous studies have found to have links to bipolar disorder. 

The second most significant module also included mostly downregulated genes. While it did not survive correction for multiple testing, it included a number of individual genes enriched in synaptic membrane pathways genes as well as TAMALIN, the most significant differentially expressed module gene, which has a role in group 1 metabotropic glutamate receptors at synapses. 

The researchers additionally examined whether loci previously associated with bipolar disorder included significant expression quantitative trait loci. After conditional analyses, the researchers found that about a third of the loci reported by the Psychiatric Genomics Consortium contained a significant QTL. This analysis highlighted roles for SCN2A and GRIN2A, which encode membrane proteins involved in neuronal signaling. SCN2A in particular encodes the alpha subunit of a voltage-gated sodium ion channel that is highly expressed in the brain, especially in excitatory glutamatergic neurons. SCN2A has previously been implicated in early brain development disorders and autism spectrum disorder.

"By identifying these individual genes, we can start to define the molecular changes that cause severely erratic moods," Hyde said. "Down the road, these findings hold the promise of new treatments targeting the abnormal chemical composition in the brains of individuals who suffer with bipolar disorder."