Gene Variants May Contribute to Bipolar Illness by Changing Brain

Two genes are known to influence neuronal firing by modulating calcium and sodium channel functions, respectively. Both affect nerve activation and nerve connectivity in the brain. One gene, called CACNA1C, is located on chromosome 12. The other gene, ANK3, is located on chromosome 10.

One variant in the CACNA1C gene and one variant in the ANK3 gene have been linked with bipolar disorder. A brain area involved in the processing of facial emotions has also shown an association with bipolar disorder. Facial affect is processed mainly in a right-sided network that involves occipital and temporal regions of the ventral visual pathway within the inferior occipital gyrus, fusiform gyrus, amygdala, and ventral prefrontal cortex.

Therefore, Sophia Frangou, M.D., Ph.D., of the Icahn School of Medicine at Mount Sinai in New York City, and colleagues decided to evaluate whether having the CACNA1C gene variant linked with bipolar disorder as well as the ANK3 gene variant also linked with the illness showed a relationship with the brain area involved in processing facial emotions.

Their study included 87 subjects—41 with bipolar disorder and 46 healthy controls. Some of the bipolar subjects had the CACNA1C gene variant of interest and some did not. Some of the healthy controls had the ANK3 gene variant of interest and some did not.

The researchers used functional MRI to analyze the activity of the facial-affect-processing area of the subjects’ brains while they were viewing emotionally provocative faces. The researchers then assessed whether they could find an association between the two gene variants of interest and facial-affect-processing brain activity.

They did find such a link in both controls and bipolar subjects. However, the associations were somewhat different between the two groups.

In control subjects, looking at emotionally arousing faces increased activity in the entire facial-affect-processing region of the brain. And those controls who had either of the gene variants of interest showed even more activity in the facial-affect-processing region than did controls without the gene variants.

In bipolar disorder subjects, in contrast, looking at emotionally arousing faces led to hypo-activation in the ventral prefrontal cortex part of the facial-affect-processing region. And this abnormality was exacerbated in bipolar disorder subjects who had either of the gene variants of interest.

The findings thus suggest two things—first, that these gene variants act on the facial-affect-processing region of the brain in both healthy individuals and those with bipolar disorder, and second, that the variants might contribute to the bipolar disease process by acting on this brain region. How the variants might actually do so, though, remains to be determined.

The findings were published online October 9 in JAMA Psychiatry.

The research was funded by the Brain and Behavior Research Foundation. ■