Letter to the Editor | Published:

The CACNA1C risk variant for bipolar disorder influences limbic activity

Molecular Psychiatry volume 15, pages 11261127 (2010) | Download Citation

An enhanced limbic activity, particularly in the amygdala, is one of the most consistent findings in bipolar disorder. Here, we show that healthy carriers of the genome-wide-supported (rs1006737) risk allele for bipolar disorder display increased amygdala activity in response to reward.

Fluctuations in mood and emotions are inherent to human nature. Excessive deviations from normal, however, are defined as mood disorders. Bipolar disorder, which is characterized by emotional changes and mood swings from manic highs to depressive lows, has a high heritability of 60–80% and is genetically the most extensively studied mood disorder to date. Genome-wide significant association between bipolar disorder and a variant (rs1006737) in the CACNAC1C gene, which encodes the alpha subunit of the L-type voltage-dependent calcium channel CAv1.2, has been found in a meta-analysis of several large independent genome-wide association studies.1 In addition, this variant has recently also been reported to have a role in depression and schizophrenia.2

We sought to test the impact of this risk variant on core endophenotypes of bipolar disorder using an imaging genetics approach in healthy individuals. Investigating the effects of risk variants on such endophenotypes in healthy individuals is a useful strategy that has repeatedly proven to be successful (for example, see Esslinger et al.3), as it is not hampered by confounding variables that are typically present in patients (for example, medication, duration of disorder and epistasis with other risk variants).

For bipolar disorder, such core endophenotypes include the dysmodulation of motivation and reward,4 as well as functional abnormalities in brain regions underlying emotional processing, especially in the amygdala.5 An enhanced amygdala activity is one of the most consistent findings from neuroimaging studies in symptomatic and remitted bipolar patients.6, 7 As the amygdala is activated in response to reward,8 functional magnetic resonance imaging (fMRI) paradigms assessing reward-related brain activations provide the opportunity to investigate both the dysmodulation of motivation and reward and functional abnormalities in emotional processing brain regions, such as the amygdala.

To assess these endophenotypes, we used a probabilistic reward reversal learning task during fMRI. This task has been shown to activate brain regions associated with reward and emotional processing,9 and has previously been used in imaging genetics.10 We adapted the task to foster amygdala activity in response to monetary reward (see Supplementary Material for details).

A total of 64 healthy volunteers of German descent were genotyped for the CACNA1C rs1006737 variant. Neither the volunteers nor their first- and second-degree relatives had ever suffered from a major mood disorder or schizophrenia, according to a structured clinical interview conducted by a psychologist. Seven of the study participants were rs1006737 AA homozygotes, 26 were rs1006737 AG heterozygotes and 31 were rs1006737 GG homozygotes (in Hardy–Weinberg equilibrium: χ2=0.19, d.f.=1, P=0.77). Owing to the small number of AA individuals, we pooled subjects carrying at least one risk allele (AA homozygotes and AG heterozygotes: N=33) and compared them with GG homozygotes (GG; N=31). Both groups were comparable with respect to demographic variables (see Supplementary Material for details).

For fMRI, a 3.0-T system acquired functional scans with an echoplanar imaging sequence optimized to detect BOLD (blood oxygen level-dependent) response changes in subcortical brain structures, such as the amygdala. fMRI data analysis was performed with SPM2 (Wellcome Trust Centre for Neuroimaging, London, UK; http://www.fil.ion.ucl.ac.uk/spm), using general linear model analysis to identify genotype effects on the neural response to reward (see Supplementary Material for details).

In comparison with GG homozygotes, carriers of the CACNA1C rs1006737 risk allele (AA/AG) showed an enhanced BOLD response in the right amygdala to monetary reward (see Figure 1). This effect was also observed when comparing the three single genotype groups (AA, AG and GG), suggesting a gene–dose effect (see Supplementary Material for details). This genotype effect in healthy individuals is very similar to findings from comparative neuroimaging studies that compared patients with bipolar disorder and healthy controls, namely, an enhanced limbic activation in response to emotional stimuli in patients.7

Figure 1
Figure 1

Increased amygdala activity (t=4.12; z=3.86; P<0.05 (FWE-corrected for ROI); x=27, y=0, z=−24; k=20 voxels) in rs1006737 AA homozygotes and AG heterozygotes (N=33) as compared with rs1006737 GG homozygotes (N=31) in response to reward delivery. FEW, family-wise error; ROI, region of interest.

It is not yet known whether the CACNA1C rs1006737 variant itself or a variant that is in linkage disequilibrium with it is causally linked to bipolar disorder. The present findings, however, show that variation at this locus has a significant impact on limbic activation in response to emotional stimuli.


  1. 1.

    , , , , , et al. Nat Genet 2008; 40: 1056–1058.

  2. 2.

    , , , , , et al. Mol Psychiatry 2009; e-pub ahead of print 21 July 2009; doi: 10.1038/mp.2009.49.

  3. 3.

    , , , , , et al. Science 2009; 324: 605.

  4. 4.

    , , , , . Biol Psychiatry 2006; 60: 93–105.

  5. 5.

    , . Schizophr Bull 2007; 33: 893–904.

  6. 6.

    , , , . Psychiatr Clin North Am 2005; 28: 443–467.

  7. 7.

    , . Int Rev Psychiatry 2009; 21: 357–367.

  8. 8.

    , , . Neuroscientist 2004; 10: 260–268.

  9. 9.

    , , , . Neuroimage 2005; 26: 609–618.

  10. 10.

    , , , , , . J Neurosci 2009; 29: 3695–3704.

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Author information


  1. Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Mannheim, Germany

    • M Wessa
    • , J Linke
    • , O Grimm
    •  & A V King
  2. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany

    • S H Witt
    • , V Nieratschker
    •  & M Rietschel
  3. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany

    • C Esslinger
    • , P Kirsch
    •  & O Grimm
  4. Department of Neurology, Universitätsklinikum Mannheim, University of Heidelberg, Mannheim, Germany

    • M G Hennerici
    •  & A Gass
  5. Neurology/Neuroradiology, University Hospital Basel, Basel, Switzerland

    • A Gass


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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to M Wessa.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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