Uncovering the genetics of bipolar disorder

The study, published today in Nature Neuroscience, explores how changes in DNA (or genetic 'variants') influence the likelihood of developing bipolar disorder.

Through this work, researchers from the Icahn School of Medicine at Mount Sinai (New York), along with contributing author Dr Jonathan Coleman from the Institute of Psychiatry, Psychology & Neuroscience at King’s College London, aim to advance our understanding of bipolar disorder and inform potential therapies for treating it.

Bipolar disorder is a mental illness that significantly affects mood, leading to both manic episodes (extreme highs) and depressive dips (extreme lows). Currently, over 1 million people live with bipolar in the UK, with fewer than half diagnosed partly due to stigma and a lack of awareness of the condition.

It is well understood that the disorder is heritable, and so can be passed down to children from parents. Past studies suggest a large contribution of genetic factors to the disease, resulting from genetic variations, but the precise mechanisms that underpin how and why it occurs are still largely unknown.

Explaining genetic variation

There are always genetic variations, or differences in DNA, among individuals of the same species. In humans, this leads to differences in traits such as hair colour, skin colour and blood type.

In terms of disease, although genetic factors on the whole do not cause psychiatric disorders, they can increase a person’s risk of developing them. Many genes often act together to elevate this risk.

As well as this, specific combinations of differences in the DNA can influence the chance of a person developing particular diseases. In other words, part of the reason why one person develops a disease, and someone else does not, could be due to genetic variations. Understanding these genetic differences could help researchers estimate a person’s risk of developing a disorder and support more effective treatments.

Fine-mapping methods to identify bipolar disorder risk genes

The largest genome-wide association study into bipolar disorder was previously carried out by the Psychiatric Genomics Consortium (PGC), involving over 40,000 people with bipolar and identifying 64 regions of DNA linked with the disorder.

However, pinpointing the specific genes or variants within these DNA regions has remained a major challenge until now. Dr Coleman explains, "Variants tend to group together in the same region of DNA, and so it is difficult to tell which variant is having the effect (i.e. the causal variant)".

Dr Coleman and his team have made huge progress in this area by using computational fine-mapping methods, a process increasingly used by geneticists to identify the causes of a given disease or trait.

"We combined several statistical methods and information about variant effects in the body to identify the most likely causal variants", Dr Coleman explains. "We looked at 64 regions of DNA and found 22 variants that might affect how bipolar disorder is developed."

These findings could help to explain how genes and variants can increase a person's risk of developing bipolar disorder, as well as the way that the illness changes and progresses over time. By strengthening insight into the genetic factors involved, it could then become possible to design more effective treatments.

Dr Coleman adds, "Changes in DNA affect the body and make some people more susceptible to developing bipolar disorder. Understanding how this occurs will help us to identify various body processes that we could target with innovative therapies, such as new drugs to treat the illness. The study's findings could also be used to design preventative and intervention measures for those at-risk of developing bipolar disorder."

Commenting on his future plans, Dr Coleman says, "I am currently completing similar work in depression, which is also funded by the Foundation. I hope to expand this approach into other psychiatric disorders, like post-traumatic stress disorder and anxiety.

In addition, one of the major limitations of this work is that it is primarily focused on people whose ancestors came from North and Western Europe. Developing new approaches that can be truly global is another vital next step."

While further research is needed before new and improved therapies for bipolar are implemented, there is a lot of scope for progress. Continued work in this field could help to provide more opportunities for therapeutic intervention, improving the lives of people diagnosed with serious mental illness.

Read the full paper: https://www.nature.com/article...