genomic aspects of bipolar disorder as a neurodegenerative disorder

for nearly 2,500 years, mood disorders have been described as one of the most common illnesses of mankind, but only recently have they commanded major public health interest. the world health organization (who) has ranked depression fourth in a list of the most urgent health problems worldwide. bipolar disorder (bd), as a mood disorder, is common, and is among the most important, serious, and one of the most difficult to diagnose among all psychiatric disorders. bipolar disorders consist of at least one hypomanic, manic, or mixed episode. clinical bd is viewed as a physical and psychic disease process having a neuropathological basis, although a clear understanding of its ethiopathology is still missing. current evidence indicates a significant genetic role in the causation of bd. however, it is not known exactly what is inherited, and biological endophenotypes have not been delineated. there is also now evidence that neurodegenerative process plays an important role in bd. the aim of this paper is to review the evidence of neurodegenerative model of bd and its genomic aspects briefly. although, many theories have been put forth regarding the origin of bd, it can be hypothesized that this disorder is a common polygenic neurodegenerative disorder in distinct populations and is likely governed by a number of different risk factors. although the mode of inheritance is not fully known, bd is highly heritable. the bipolar inheritance might translate into affective dysregulation, involving over- and underreactivity to life situations, circadian events, and biological stressors. both clinical and genetic investigations have emphasized the affective dysregulation underlying bipolar disorder can manifest itself in euphoria, irritability, depression, panic attacks, and social anxiety. such tendencies are observed among both patients and their first degree relatives. genetic heterogeneity is likely and may involve inheritance of a single dominant gene with variable penetrance in some families or specific subtypes or oligogenic inheritance in the majority of cases. the mode of transmission in bd is unknown and most likely complex and non-mendelian. multipoint analysis suggests that eight regions of linkage with p-values < 0.01 (2p21, 2q14.3, 3p14, 5q33, 7q36, 10q23, 16q23 and 20p12) are involved in aetiology of mood disorders. variations/polymorphisms in 12 specific genes are involved in aetiology of bd, including klf12, aldh1a1, a2bp1, ak3l1, rorb, rora, bdnf, arntl, gsk3b, disc1, nrg1, and htr2a. there is now evidence that neurodegenerative process plays an important role in mood disorders, including bd. the purported functions of medial temporal lobe structures suggest their involvement in the pathophysiology of bd. the previous reports of abnormalities in the volume of the amygdala and hippocampus in patients with bd have been limited to adult samples. however, evidence shows that the structural abnormalities in the amygdala and hippocampus are common to adolescent and adult bd. these common abnormalities may represent the expression of a common genetic vulnerability to bd. two primary drugs used to treat bd are lithium and valproate. emerging evidence supports the notion that both mood stabilizers have neuroprotective effects. the neuroprotective mechanisms involve inactivation of nmda receptors through inhibition of nr2b tyrosine phosphorylation, activation of cell survival factors such as the pi3k/akt signalling pathway, and induction of neurotrophic/neuroprotective proteins, including bdnf, hsp, and bcl-2. the molecular targets likely involve gsk-3 and hdac for lithium and valproate, respectively. in huntingtons disease, short-term lithium pretreatment is sufficient to protect against dna damage, caspase activation, and apoptosis of striatal neurons and this neuroprotection is concurrent with bcl-2 induction. moreover, lithium treatment increases cell proliferation near the site of striatal injury. thus, lithium and valproate (mood stabilizer) are potential drugs for treating some forms of neurodegenerative diseases. recent findings implicate epigenetic modifications, including acetylation, methylation, ubiquitination, phosphorylation and sumolyation in the aetiology of neurodegenerative and psychiatric disorders. epigenetic remodeling is crucial to cellular differentiation, development and behaviour including learning and memory. the epigenome is responsive to synaptic activity and provides a link between experience, genetic predisposition, and changes in neural function. epigenetic dysregulation is a common theme in disorders of synaptic plasticity and cognition including neurodegenerative disorders (e.g., huntington and parkinson), and mood disorders (e.g., bd). a vast body of evidence supports a neurodegenerative model that has been used to explain the aetiology and course of bd. evidence suggests a high degree of heritability for bd and a number of candidate genes that may be involved in the development of bd. these genes are involved in sleep regulation, memory formation, emotion regulation, and motor behaviour.