Gene Study Reveals Clues to Bipolar Disorder Physiology

A large genomic study suggests that defective sodium and calcium channels in neurons may explain an important part of the physiological mechanism of bipolar disorder.

A group of researchers in the United States, United Kingdom, and Canada found significant association between bipolar disorder and genetic variations in two genes involved in the formation of a sodium channel and a calcium channel, ANK3 and CACNA1C.

The study, the largest genomic study on bipolar disorder to date, tested 1.8 million genetic polymorphisms in 4,387 bipolar patients and 6,209 control subjects from three studies to identify genetic variations that may be significantly associated with the illness.

Sodium and calcium channels are “ion gates” made of proteins embedded in cell membranes. They regulate the amount of electrically charged sodium and calcium ions flowing in and out of nerve cells as they open and close. This process is a fundamental part of generating and transmitting signals throughout the nervous system.

The ANK3 gene is expressed as the ankyrin G protein, a type of protein involved in regulating the sodium channels in nerve cell membranes that open and close according to electrical impulses. They are known as voltage-gated channels because they open and close depending on the difference in electric charges within and outside of the cell membrane. Several single nucleotide polymorphisms across the chromosomal region for the ANK3 gene were found to be strongly associated with bipolar disorder (p=9.1×10^-9), meaning that bipolar patients are much more likely to have defects in this protein than those with-out the illness.

The second strongest genetic association with the illness was found in a noncoding region (the third intron) of the CACNA1C gene, which codes for a subunit of the L-type voltage-gated calcium channel protein. Additional regions associated with bipolar disorder were also identified.

Scientists have already suspected ion channel problems in the mechanism of bipolar disorder, as both ANK3 and subunits of the calcium channel are downregulated in the brain in mice after lithium treatment. The findings in this genomic study have provided strong and independent corroboration for this theory.

The study was published online in Nature Genetics on August 17 and supported by grants from a number of government agencies in the United States, Australia, the United Kingdom, and Ireland and several private sources.

An abstract of “Collaborative Genome-wide Association Analysis Supports a Role for ANK3 and CACNA1C in Bipolar Disorder” is posted at<www.nature.com/ng/journal/v40/n9/abs/ng.209.html>.▪