Independent modulation of engagement and connectivity of the facial network during affect processing by CACNA1C and ANK3 risk genes for bipolar disorder

JAMA Psychiatry. 2013 Dec;70(12):1303-11. doi: 10.1001/jamapsychiatry.2013.2099.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Affect / physiology*
  • Ankyrins / genetics*
  • Bayes Theorem
  • Bipolar Disorder / genetics*
  • Bipolar Disorder / physiopathology
  • Brain / physiopathology*
  • Calcium Channels, L-Type / genetics*
  • Connectome / instrumentation
  • Connectome / methods
  • Cross-Sectional Studies
  • Face / physiology
  • Facial Expression
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Magnetic Resonance Imaging / instrumentation
  • Magnetic Resonance Imaging / methods
  • Male
  • Middle Aged
  • Nerve Net / physiopathology
  • Polymorphism, Single Nucleotide / genetics


  • ANK3 protein, human
  • Ankyrins
  • CACNA1C protein, human
  • Calcium Channels, L-Type