Bipolar 1 Disorder

Abstract

This project investigates the genetic and molecular underpinnings of Bipolar 1 Disorder (BP-1), focusing on single nucleotide polymorphisms (SNPs) in the BDNF, CACNA1C, and ANK3 genes. BP-1 is characterized by extreme mood swings between manic and depressive states, with symptoms including high energy, irritability, and suicidal ideation. Environmental factors, such as stress and substance abuse, exacerbate the disorder's severity and frequency. The BDNF gene, responsible for brain-derived neurotrophic factor, regulates neuroplasticity and synaptic function. Mutations in BDNF disrupt neurogenesis and neurotransmitter balance, contributing to mood instability. CACNA1C, encoding a calcium channel subunit, affects neuronal excitability and neurotransmitter release, with mutations causing hyperactive calcium signaling linked to manic episodes. ANK3 plays a role in neuronal structure and action potential regulation, and mutations impair sodium and potassium ion channel function, disrupting neuronal communication. Treatment typically involves mood stabilizers such as lithium and lamotrigine, which regulate neurotransmitter levels and neuronal activity. Lithium reduces dopamine and glutamate activity, while lamotrigine stabilizes neuronal membranes. However, treatment outcomes remain inconsistent, highlighting the need for personalized therapeutic strategies. The study underscores the need for deeper research into the gene-environment interactions influencing BP-1, with the goal of developing targeted therapies addressing the genetic and neurobiological roots of the disorder.

Optimal circuitry arrangements and behavior, resulting in plasticity and survival.
(Figure representation created by the authors:Oliver Bodden-Howard and Marissa Miller)

Background

Bipolar 1 disorder (BP-1) is a complex mental disorder defined by extreme shifts in mood oscillating between mania and depression. The occurrence of at least one manic episode that could be followed or preceded by a hypomanic or depressive episode is required for a diagnosis. In manic episodes, BP patients experience extreme elevations in mood, resulting in an irritable or euphoric state accompanied by high energy and activity levels, an increase in risky behavior, an inflated sense of self-esteem and grandiosity, and a decreased need for sleep. Depressive episodes, on the other hand, result in extreme lows in mood, such as feelings of sadness, anxiety, or hopelessness. Eioloty of BP-1 is not very well understood and therefore comprehensive understanding of the disease is warranted for effective management of the disease.

Problem Statement

Globally, the prevalence of Bipolar I Disorder is around 0.6%, however in the U.S. the prevalence rate is higher at around 1.0%. The precise etiology of BP-1 remains elusive; however, research thus far suggests it is a combination of environmental, genetic, and neurophysiological factors.

Research Hypothesis

Single-nucleotide polymorphisms (SNPs) in the genes BDNF, CACNA1C, and ANK3 may play a collective pathophysiological role in the mechanisms of bipolar disorder. A patient affected by these SNPs may see satisfactory results using a treatment combination of lamotrigine and lithium.

Results

Genes contributing to increased risk of BP-1
(Figure representation created by the authors:Oliver Bodden-Howard and Marissa Miller)

From a network of many interacting genes we identified ANK3, BDNF, and CACNA1C have a combined impact on the neurophysiology of BP-I. These genes affect signalling pathways P13K/AKT, GSK-beta, and CAMKK2 and these may be rendered defective via influence of risk genes on molecular functions and chemical interactions.
All these 3 genes interact with Brain derived Neurotrophic factor (BDNF) which is a very critical protein for neuron cells survival and growth. Changes in the BDNF levels, structure are linked to BP-1 as it leads to changes in cognitive activity, mood instability etc. Research has indicated that levels of BDNF change during depressive and manic phases as it leads to disruption of the brain's ability to adapt. Such alterations lead to inappropriate neuronal circuitry in hippocampus and prefrontal cortex which are the two primary regions of the brain linked with impaired emotional processing.
We further researched available treatment for BP-1 and how it works. Based on our research- these 3 genes based treatment could increase treatment options for the disease.

Distorted structure and function of Brain derived Neurotrophic Factor (BDNF).
(Figure representation created by the authors:Oliver Bodden-Howard and Marissa Miller)

Conclusion

Dysfunctions in BDNF, CACNA1C, and ANK3, caused by single nucleotide polymorphisms rs6265, rs1006737, and rs10994336, play a collective role in the pathophysiology of BP-1, resulting in dysfunctional P13K/AKT, GSK-beta, PLC-Gamma-1 and CAMKK2 signaling pathways, structural deficits in the brain and synaptic plasticity, and an excitatory/inhibitory imbalance of neurotransmitters. As stated previously, a combination of lithium and lamotrigine could be incredibly beneficial for patients who are non-responders to monotherapy, as it focuses on both poles of the disorder. Despite this, treatment outcomes are still suboptimal. Further investigation into the interaction between the SNPs of these genes and environmental factors is needed to develop targeted therapies and understand more about the mechanisms and treatment response of BP-1