Exploring the underlying mechanisms behind brain disorders
Genome-wide association studies (GWASs) screen thousands of genetic variants, comparing the genomes of people with and without specific traits to identify variants associated with disease. These studies have led to deep insights into many diseases, including brain disorders. Yet despite their potential, GWASs are still limited in identifying the mechanisms underlying brain disorders, in part because the same disorder can arise from various combinations of risk variants in different patients. In the GWAS2FUNC project, which received support from the European Research Council(opens in new window), a collaboration of researchers aimed to bridge this knowledge and application gap, through the development of new tools to assess the variations present across a range of neurological conditions.
Gene expression signatures at the cellular level
The project was able to develop a method that integrates GWAS results with information on gene expression signatures at the cellular level. Another tool was developed to investigate the potential biological substructure of a disease based on patterns of genomic correlations. “We have also just recently released FLAMES, a novel tool that improves on predicting what is the most likely causal gene based on GWAS results,” says Danielle Posthuma(opens in new window), a statistical geneticist at the Vrije Universiteit Amsterdam(opens in new window) in the Netherlands, and the GWAS2FUNC principal researcher. “This helps in defining possible targets for follow-up studies.” Through the GWAS2FUNC project, Posthuma was able to develop these tools based on previous iterations, and to validate them extensively using simulations. “These tools are able to generate hypotheses with respect to possible underlying biological mechanisms of disease,” notes Posthuma. “These hypotheses still need to be validated in functional experiments and ultimately in clinical trials.”
Publicly available methodological innovations
These methodological innovations have been made publicly available online. The tools are currently being used by other researchers, as well as by the GWAS2FUNC team through several ongoing projects. For instance, the tools assist in setting up functional experiments to investigate the biological mechanisms of brain disorders, such as Alzheimer’s, dementia, schizophrenia and addiction. The researchers also hope to advance clinical practice in several ways; firstly, by helping to improve predictions of who is at greater risk of developing a certain disease, which can aid in early prevention strategies. Secondly, the tools will help guide personalised and potentially more effective treatment plans, by predicting how patients that already have disorders will benefit from specific therapeutics. By generating more insight into underlying disease mechanisms, these tools may help in setting up novel treatment strategies or pharma studies.
Developing the tools through large-scale initiatives
The researchers plan to continue improving the tools, using new data that becomes available over the coming years. This includes other large-scale initiatives such as those run at the Allen Brain Institute(opens in new window) in Seattle, United States, where researchers are generating large databases of RNA molecules produced in the brain to gain deeper insights into the diversity of cell types. The GWAS2FUNC team is also working to develop methods to integrate different levels of information from other fields to further improve on interpreting results from GWASs. Finally, Posthuma is also collaborating closely with scientists to carry out functional experiments that can test the hypotheses generated using the latest GWAS results. “This is very exciting,” she adds. “The aim is to dive deep into the underlying biology of many brain-related diseases.”
Keywords
GWAS2FUNC, mechanisms, brain disorders, tools, simulations, methodological innovations
