Lithium's main treatment for bipolar disorder was approved a half-century ago but didn't help all patients and has significant side effects. In part, little progress has been made in finding better therapies because scientists don’t fully understand how the condition arises or exactly how lithium improves symptoms when it does work.
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A genetic study involving thousands of people with bipolar disorder has revealed new insight into the condition’s molecular underpinnings.
Led by scientists at Harvard Medical School and the Broad Institute of MIT and Harvard, the international effort pinpoints a gene called AKAP11 as a vital risk factor for both bipolar disorder and schizophrenia.
The findings may provide clues to how lithium works, as the AKAP-11 protein is known to interact with a molecular pathway modified by the drug.
While many common genetic variants of minor effects have been discovered, AKAP11 is the first gene found to have a significant impact on bipolar disorder risk.
The findings pave the way for a better understanding of the condition's causes and potential new therapies. This result has already kicked off recent studies of the disorder in cells and animals, focusing on molecular mechanisms that can lead to the identification of biomarkers to match patients with treatments and develop novel therapies.
The study was published online in Nature Genetics.
“This work is exciting because it’s the first time we’ve had a gene with large-effect mutations for bipolar disorder,” said Steven Hyman, Harvard University Distinguished Service Professor of Stem Cell and Regenerative Biology and director of the Stanley Center for Psychiatric Research at the Broad. “This is an important step towards the kind of research into disease mechanisms that, across the history of medicine, has underwritten successful therapeutics.”
The big study, big effect
Bipolar disorder is a severe, heritable mood disorder that affects approximately 1 per cent of people and often begins in early adulthood. A better understanding of the condition’s biological roots could lead to more effective therapies that can improve quality of life.
The HMS and Broad scientists partnered with colleagues around the world in the Bipolar Exome Consortium to identify rare differences in the DNA sequence that alter proteins with the hope of discovering ones with a significant impact on disease risk.
Although rare mutations occur in a minority of patients, the strong impact on disease risk means that they can illuminate the biological mechanisms on a broader scale.
The researchers compared the exomes, or protein-coding portion of the genome, of roughly 14,000 people with bipolar disorder to 14,000 healthy controls. They found that people with the condition were more likely to carry gene variants that result in abnormally truncated, dysfunctional proteins. Some of these variants were in genes already known to be associated with risk for schizophrenia, another severe mental illness that often begins after adolescence.
The team next incorporated the results of a large-scale study conducted by the Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) consortium. They combined the exome sequences of 24,000 people with schizophrenia who participated in the SCHEMA study with those of 14,000 people with bipolar disorder and compared the series to those of healthy controls.
This analysis revealed rare protein-truncating variants in the AKAP11 gene that raise disease risk several-fold, making it the strongest genetic risk factor found for bipolar disorder.
“The AKAP11 variants don’t contribute much to risk among the population as a whole, but the real value is what they reveal about the roots of disease, and that's why we're really focused on them,” said senior author Benjamin Neale, HMS associate professor of medicine at Massachusetts General Hospital.
Neale is also director of genetics at the Stanley Center and co-director of the Medical and Population Genetics program at the Broad, where he is an institute member.
The team found that the protein product of AKAP11 interacts with another protein called GSK3B, a molecular target of lithium that is a potential mechanism of efficacy. Thus, the discovery offers intriguing clues to lithium’s effects on the body that may shed light on the action of lithium and lead to the identification of other therapeutic targets.
New variants, new models
To explore the molecular and behavioural effects of the AKAP11 gene variants uncovered in the study, the team is now creating cellular and animal models carrying an altered form of the gene. It will be the first time scientists employ research models harbouring the same variants found to increase risk in humans.
The researchers are also exploring whether AKAP-11 or one of its molecular partners could serve as a biomarker for the condition, to aid in the diagnosis or help ensure that future clinical trials include patients who are most likely to benefit from a particular therapy.
The team aims to uncover more genetic risk factors for bipolar disorder.
“Ideally, we’d like to find risk variants across the whole genome, which will give us the best chance of coming up with treatments for everyone,” said Hyman. “This is a first, and we're hoping we'll find many more genetic factors. It will take a lot of exome sequencing, but it is fascinating.”
Source: HMS