Original Investigation |

Independent Modulation of Engagement and Connectivity of the Facial Network During Affect Processing by CACNA1C and ANK3 Risk Genes for Bipolar Disorder

Danai Dima, PhD1; Jigar Jogia, PhD1; David Collier, PhD2; Evangelos Vassos, MD, PhD2; Katherine E. Burdick, PhD3; Sophia Frangou, MD, PhD3
[+] Author Affiliations
1Section of Neurobiology of Psychosis, Department of Psychosis Studies, Institute of Psychiatry, King’s College London, London, England
2Social Genetic and Developmental Psychiatry, Institute of Psychiatry, King’s College London, London, England
3Department of Psychiatry, Icahn School of Medicine at Mt Sinai, New York, New York
JAMA Psychiatry. 2013;70(12):1303-1311. doi:10.1001/jamapsychiatry.2013.2099.
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Importance  Genome-wide association studies (GWASs) indicate that single-nucleotide polymorphisms in the CACNA1C and ANK3 genes increase the risk for bipolar disorder (BD). The genes influence neuronal firing by modulating calcium and sodium channel functions, respectively. Both genes modulate γ-aminobutyric acid–transmitting interneuron function and can thus affect brain regional activation and interregional connectivity.

Objective  To determine whether the genetic risk for BD associated with 2 GWAS-supported risk single-nucleotide polymorphisms at CACNA1C rs1006737 and ANK3 rs10994336 is mediated through changes in regional activation and interregional connectivity of the facial affect–processing network.

Design, Setting, and Participants  Cross-sectional functional magnetic resonance imaging study at a research institute of 41 euthymic patients with BD and 46 healthy participants, all of British white descent.

Main Outcomes and Measures  Blood oxygen level–dependent signal and effective connectivity measures during the facial affect–processing task.

Results  In healthy carriers, both genetic risk variants were independently associated with increased regional engagement throughout the facial affect–processing network and increased effective connectivity between the visual and ventral prefrontal cortical regions. In contrast, BD carriers of either genetic risk variant exhibited pronounced reduction in ventral prefrontal cortical activation and visual-prefrontal effective connectivity.

Conclusions and Relevance  Our data demonstrate that the effect of CACNA1C rs1006737 and ANK3 rs10994336 (or genetic variants in linkage disequilibrium) on the brain converges on the neural circuitry involved in affect processing and provides a mechanism linking BD to genome-wide genetic risk variants.

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Figure 1.
Effect of Bipolar Disorder (BD) Risk Genes on Facial Affect Processing

The effect of CACNA1C rs1006737 and ANK3 rs10994336 risk variants on the inferior occipital gyrus (IOG), fusiform gyrus (FG), amygdala (AMG), and ventral prefrontal cortex (VPFC) function during facial affect processing in patients with BD and healthy controls (HC) in mean signal intensity (reported as a percentage of whole-brain volume signal change).

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Figure 2.
Results of Dynamic Causal Modeling (DCM) and Bayesian Model Averaging in Healthy Controls and Patients With Bipolar Disorder (BD)

A, Optimal DCM selection. Models compromised by a 4-area DCM are specified with bidirectional endogenous connections among all regions (inferior occipital gyrus [IOG], fusiform gyrus [FG], amygdala [AMG], and ventral prefrontal cortex [VPFC]) and a driving input of all faces into the IOG. For ease of display, affect modulations are labeled as facial affect (black dot) but correspond to the distinct modulations of fearful, angry, and sad faces. B, Alterations in effective connectivity within the facial processing network established by Bayesian model averaging across all models considered. For controls, the bold black arrows indicate significantly increased connectivity from the IOG to the VPFC modulated by the CACNA1C (rs1006737) and ANK3 (rs10994336) risk variants. For patients with BD, the dashed arrows indicate significantly decreased connectivity from the IOG to the VPFC modulated by the CACNA1C (rs1006737) and ANK3 (rs10994336) risk variants. Black solid arrows indicate all other network connections.

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