Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains

Abstract

Recent advances in genome-wide association studies are pointing towards a major role for voltage-gated ion channels in neuropsychiatric disorders and, in particular, bipolar disorder (BD). The phenotype of BD is complex, with symptoms during mood episodes and deficits persisting between episodes. We have tried to elucidate the common neurobiological mechanisms associated with ion channel signaling in order to provide a new perspective on the clinical symptoms and possible endophenotypes seen in BD patients. We propose a model in which the multiple variants in genes coding for ion channel proteins would perturb motivational circuits, synaptic plasticity, myelination, hypothalamic-pituitary-adrenal axis function, circadian neuronal rhythms, and energy regulation. These changes in neurobiological mechanisms would manifest in endophenotypes of aberrant reward processing, white matter hyperintensities, deficits in executive function, altered frontolimbic connectivity, increased amygdala activity, increased melatonin suppression, decreased REM latency, and aberrant myo-inositol/ATP shuttling. The endophenotypes result in behaviors of poor impulse control, motivational changes, cognitive deficits, abnormal stress response, sleep disturbances, and energy changes involving different neurobiological process domains. The hypothesis is that these disturbances start with altered neural circuitry during development, following which multiple environmental triggers may disrupt the neuronal excitability balance through an activity-dependent molecular process, resulting in clinical mood episodes.

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

“…This is in line with previous genetic evidence pointing to a key etiologic role of potassium channels, in particular, in BD(Judy and Zandi, 2013), which could be explained by their role in multiple neurobiological mechanisms involved in the development of psychiatric disorders such as regulation of the dopaminergic circuits, synaptic plasticity, and myelination(Balaraman et al, 2015). …”

“…Performing pathway analysis based on the full association results shows enrichment of genes involved in response to potassium ions, including potassium voltage-gated channel subfamily members and a number of genes regulated by cellular potassium concentration. This is in line with previous genetic evidence pointing to a key etiologic role of potassium channels, in particular, in BD(Judy and Zandi, 2013), which could be explained by their role in multiple neurobiological mechanisms involved in the development of psychiatric disorders such as regulation of the dopaminergic circuits, synaptic plasticity, and myelination(Balaraman et al, 2015).…”

Genetic Associations between Voltage-Gated Calcium Channels and Psychiatric Disorders

“…Furthermore, the minor allele for rs1006737 (A) is associated with increased methylation of CpG islands located within intron 3 [162]. Imaging studies have shown associations of rs1006737 with changes in structure and activity of brain regions related to emotion processing, memory formation and cognition, including hippocampus, inferior occipital fusiform gyrus, prefrontal cortex and amygdala [136,163,164]. For example, carriers of rs1006737 show greater thickness of the medial orbitofrontal cortex than non-carriers, and the presence of this SNP correlates with age-related caudal anterior cingulate cortex thickening [164].…”

Developmental profile of psychiatric risk associated with voltage-gated cation channel activity

“…We observed that genetic association with BD in VG-cation was distributed between calcium and potassium components. Voltage-gated potassium channels have been linked to BD through genetic studies previously (21,(53)(54)(55)(56)(57), and this represents a divergence from schizophrenia and MDD which have not shown evidence of conferring risk through potassium channels. The broad function of voltage-gated potassium channels is to control the threshold for action potentials and repolarise the membrane after firing (58).…”