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A single nucleotide polymorphism within the CACNA1C gene (rs1006737) has been found to confer increased risk of Bipolar Disorder (BD) and has been linked to altered neuronal gating and emotional behaviour. As current models of BD suggest abnormal integration within frontolimbic networks, our aim was to explore the effect of the CACNA1C genotype on prefrontal and limbic activation.
We genotyped 90 participants from the Vulnerability to Bipolar Disorder Study comprising of 41 euthymic BD patients and 49 healthy controls. Functional magnetic resonance imaging data were obtained while participants performed a fearful versus neutral facial affect processing task.
We found a significant diagnosis by genotype interaction with BD patients homozygous for the risk allele having reduced prefrontal activation compared to the other groups.
The present findings support the hypothesis that the rs1006737 polymorphism in the CACNA1C gene confers increased risk of BD by modulating amygdala and PFC activation during emotional processing.
We wished to examine whether patterns of neural engagement during emotional processing could distinguish patients with Bipolar Disorder (BD) from their relatives with Major Depressive Disorder (MDD) and their psychiatrically healthy relatives.
Functional magnetic resonance imaging (fMRI) data were collected during a sad facial affect recognition task from 41 remitted BD patients, 40 of their first degree relatives (15 of whom had MDD) and 51 healthy controls. Data were analysed in SPM5.
A) Compared to controls, all individuals with genetic predisposition to BD showed increased activation in temporal lobe regions.
B) Compared to BD patients, MDD relatives had reduced activation in the left posterior cingulate (BA31) and the orbitofrontal cortex (BA11)
C) Compared to their healthy relatives, BD patients showed increased activation in somatosensory cortices bilaterally (BA3 and BA5) and in the posterior cingulate gyrus (BA30) on the left and reduced activation in the right cerebellum and the right inferior frontal gyrus (BA47).
D) Compared to their healthy relatives, MDD relatives showed reduced activation in the left superior frontal gyrus (BA10).
Our results suggest that:
(a) genetic predisposition to BD was associated with increased activation in distal nodes of the ventral visual pathway within the temporal lobe
(b) disease expression for mood disorders was associated with reduced neural responses in the PFC
(c) resilience in healthy relatives was associated with enhanced PFC engagement
(d) loci identified showed partial specificity for different clinical phenotypes indicative of partially segregated processes underpinning disease and resilience for mood disorders.
The Met allele of the catechol-O-methyltransferase (COMT) valine-to-methionine (Val158Met) polymorphism is known to affect dopamine-dependent affective regulation within amygdala–prefrontal cortical (PFC) networks. It is also thought to increase the risk of a number of disorders characterized by affective morbidity including bipolar disorder (BD), major depressive disorder (MDD) and anxiety disorders. The disease risk conferred is small, suggesting that this polymorphism represents a modifier locus. Therefore our aim was to investigate how the COMT Val158Met may contribute to phenotypic variation in clinical diagnosis using sad facial affect processing as a probe for its neural action.
We employed functional magnetic resonance imaging to measure activation in the amygdala, ventromedial PFC (vmPFC) and ventrolateral PFC (vlPFC) during sad facial affect processing in family members with BD (n=40), MDD and anxiety disorders (n=22) or no psychiatric diagnosis (n=25) and 50 healthy controls.
Irrespective of clinical phenotype, the Val158 allele was associated with greater amygdala activation and the Met158 allele with greater signal change in the vmPFC and vlPFC. Signal changes in the amygdala and vmPFC were not associated with disease expression. However, in the right vlPFC the Met158 allele was associated with greater activation in all family members with affective morbidity compared with relatives without a psychiatric diagnosis and healthy controls.
Our results suggest that the COMT Val158Met polymorphism has a pleiotropic effect within the neural networks subserving emotional processing. Furthermore the Met158 allele further reduces cortical efficiency in the vlPFC in individuals with affective morbidity.
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