Novel genes have been identified as possible contributors to bipolar disorder. The condition, also known as manic-depressive illness, is a chronic and devastating psychiatric illness, affecting 0.5-1.6% of the general population across their lifetime. Its causes are not yet fully understood, but genetic factors are thought to play a large role.
Professor Markus Nothen of the University of Bonn, Germany, explains, “There is no one gene that has a significant effect on the development of bipolar disorder. Many different genes are evidently involved and these genes work together with environmental factors in a complex way.”
His international team analyzed genetic information from 2,266 patients with bipolar disorder and 5,028 comparable people without bipolar disorder. They merged these individuals’ information with that of thousands of others held in previous databases. Altogether, this included the genetic material of 9,747 patients and 14,278 non-patients. The researchers analyzed about 2.3 million different regions of DNA.
This highlighted five areas that appeared to be connected to bipolar disorder. Two of these were new gene regions containing “candidate genes” connected to bipolar disorder, specifically the gene “ADCY2” on chromosome five and the so-called “MIR2113-POU3F2” region on chromosome six.
The remaining three risk regions, “ANK3”, “ODZ4” and “TRANK1”, were confirmed to be linked to bipolar disorder, having been previously suspected to play a role. “These gene regions were statistically better confirmed in our current investigation, the connection with bipolar disorder has now become even clearer,” said Professor Nothen.
Full details appear in the journal Nature Communications. The authors write, “Our finding provides new insights into the biological mechanisms involved in the development of bipolar disorder.”
“The investigation of the genetic foundations of bipolar disorder on this scale is unique worldwide to date,” says study co-author Professor Marcella Rietschel. “The contributions of individual genes are so minor that they normally cannot be identified in the ‘background noise’ of genetic differences. Only when the DNA from very large numbers of patients with bipolar disorder are compared to the genetic material from an equally large number of healthy persons can differences be confirmed statistically. Such suspect regions which indicate a disease are known by scientists as candidate genes.”
One of the newly discovered gene regions, “ADCY2”, was of particular interest to Professor Nothen. This section of DNA oversees the production of an enzyme used in the conduction of signals into nerve cells. He said, “This fits very well with observations that the signal transfer in certain regions of the brain is impaired in patients with bipolar disorder. Only when we know the biological foundations of this disease can be also identify starting points for new therapies.”
Evidence from family, twin and adoption studies has previously provided strong evidence of the genetic predisposition to bipolar disorder. For example, if one monozygotic (identical) twin has bipolar disorder, the other twin has a 60% chance of also developing the condition.
Genetics expert Dr. John B Vincent of the University of Toronto, Canada, says, “Identification of susceptibility genes for bipolar disorder is the first step on a path toward improved understanding of the pathogenesis of mood disorders, with much to offer including (a) more effective and better targeted treatments, (b) earlier recognition of individuals at risk, and (c) improved understanding of environmental factors.”
But he cautions that, “No variation within a single gene can explain the majority of cases of bipolar disorder”, and the chromosomal regions affected “are typically broad.”
Dr. Vincent also points out that the recent “wave of large genome-wide association studies bipolar disorder,” have failed to replicate their results across different sample sets. He believes that much larger sample sizes are necessary. From the few studies that have pooled data from large patient cohorts, “some exciting findings of possible susceptibility loci and genes” have been made, such as DGKH, CACNA1C and ANK3.
“We’re all working toward establishing the ultimate set of genes associated with bipolar disorder, and then we can look at how they are involved in the functioning of neurons in the brain,” he says. “We need to pool results with other studies to confirm the true associations, and this requires many tens of thousands of people.”
Very recent findings are now suggesting that some genes linked to bipolar disorder are expressed differently during the manic and depressed phases of the disease. Other bipolar disorder-related genes appear to behave similarly in both mood states. These new findings also highlight three distinct areas that are impacted by bipolar disorder genes, that is, energy metabolism, inflammation and the ubiquitin proteasome system (the breakdown of proteins in bodily cells).
Combining gene expression and genome-wide data should soon provide valuable insights into the biological mechanisms of bipolar disorder, and point to more effective therapies.
Muhleisen, T. W. et al. Genome-wide association study reveals two new risk loci for bipolar disorder. Nature Communications, 12 March 2014 doi: 10.1038/ncomms4339
Xu, W. et al. Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1. BMC Medical Genetics, 4 January 2014 doi: 10.1186/1471-2350-15-2.