Researchers from the Danish psychiatry research-project iPSYCH have contributed to identify 33 new genetic variants which, as it turns out, play a role in bipolar disorder. To achieve this, they have examined DNA profiles from 413,000 people.
A number of scientific working groups are currently attempting to identify the genetic architecture underlying heritable and severe psychiatric disorders such as schizophrenia, depression and bipolar disorder.
One of these working groups is iPSYCH, Denmark’s largest research project focusing on psychiatric disorders. Together with international colleagues, they have recently examined the genetic risk factors behind bipolar disorder. The research groups have examined DNA profiles from a total of 413,000 people of European descent.
These comprise 42,000 patients with bipolar disorder together with 371,000 individuals without the disorder. By comparing the results from these two groups, the researchers have succeeded in identifying 33 genetic variants which, as it turns out, play a role in the risk of developing bipolar disorder.
More knowledge about the disorder
This means that the number of mapped genetic variants – genetic risk factors – behind bipolar disorder has more than doubled, explains one of the Danish participants in the project, Associate Professor Thomas Damm Als from the Department of Biomedicine at Aarhus University:
“In the international collaboration that we’re part of and which is focused on mapping genetic risk factors behind bipolar disorder, we’ve carried out three studies. Before we began the third study, we had knowledge of 31 risk variants – so this is a really significant increase in our knowledge of the genetic architecture of the disease.”
The results have been published in the scientific journal Nature Genetics.
The 413,000 DNA profiles that the research group has examined stem from a total of 57 European health databases – with around 7,000 profiles from iPSYCH, the Lundbeck Foundation’s Initiative for Integrated Psychiatric Research.
But what exactly are the researchers examining when they map out genetic variants in connection with a psychiatric disorder?
“On a general level we’re looking for certain patterns in the prevalence of large pieces of DNA with several variants. Over time a whole ‘library’ of these genetic variants, which can appear in different places in the genome – our DNA that is – has been built up,” says Thomas Damm Als.
Ideas for new treatment
By examining DNA from people who have a particular disease – and then comparing the results with DNA from people who are not affected by it – it is therefore possible to utilise the ‘library’ to see whether certain genetic variants are especially present in connection with the disease.
“This was how we found the 33 variants,” says Thomas Damm Als: “But before we got to this point, we had to take all 413,000 DNA samples and look for variants at eight million places in the genome. It was a huge analysis, and it was only possible because more than two hundred researchers participated in the work.”
However, the genetic variants do not provide the complete explanation of how a person develops bipolar disorder.
“They are various contributory factors, environmental factors, however, also play a role – and a similar ‘cocktail’ of hereditary and environmental factors are also underlying other psychiatric disorders such as schizophrenia and depression,” explains the researcher.
In a broad sense, the identified genetic variants can be related to brain functions. Some of the variants are thus involved in genes expressed in the brain, while others influence the signalling between nerve cells in the brain.
This knowledge broadens our understanding of bipolar disorder and may also generate ideas for the development of new medical treatments. But as the researcher emphasizes, this is in no way a more detailed explanation of bipolar disorder,
“Today, we know that bipolar disorder appear to be more heritable than e.g. depression – but how these genetic factors and environmental factors interact is something we still need to understand. And we haven’t yet identified all of the relevant genetic variants.”
The road to a better understanding of the disorder involves even more DNA studies, as a similar mapping of depression which is also presently being carried out by a large team of international researchers has demonstrated. In this study it took a long time to find genetic variants specific to depression. Only when the research group had analysed approximately 500,000 DNA profiles did they really begin to see a clearer picture.
“It’s true for all psychiatric disorders, that you need to have a certain study size to have any hope of finding genetic variants that can be considered risk factors,” says Thomas Damm Als.
Note: Bipolar disorder (formerly called manic depression) is a psychiatric disorder that typically occurs in adolescence. It leads to periods of mania or slight mania. These periods, which are characterised by unnatural exhilaration with increased energy, activity and self-esteem, are replaced by depressive periods. Manic and depressive symptoms may also occur simultaneously or with rapid shifts.1.3 per cent of men and 1.8 per cent of women are either hospitalised or receive ambulatory treatment for bipolar disorder during their life.
Background for the results
- Type of study: Case control and case cohort studies.
- External funding: The Lundbeck Foundation and several international foundations including the Stanley Foundation and NIH/NIMH. Partners: The result is a collaboration between 230 researchers, primarily from Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; The Broad Institute at Harvard and MIT together with Massachusetts General Hospital in Boston, but also including a number of other international researchers and institutions who are organised in The Psychiatric Genomics Consortium. The scientific artcle can be read in Nature Genetics.
Reference: Mullins, N., Forstner, A.J., O’Connell, K.S. et al. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nat Genet (2021). https://doi.org/10.1038/s41588-021-00857-4
Provided by Aarhus University