Identifying the genes behind mental disorders
Are there specific genes that cause mental disorders? A new genome-wide association study from Dr. Shreejoy Tripathy, Dr. Michael Wainberg, and their team has identified a list of genes that may play a role in causing major depression, bipolar disorder, and schizophrenia. They’ve also uncovered important information about the types of genes that are linked to the psychiatric disorders. We spoke to Dr. Tripathy and Dr. Wainberg to learn more about the study’s discoveries.
What are genome-wide association studies?
Genome-wide association studies are studies that measure the DNA of a large number of people and ask which genetic variants (commonly called “mutations”) are more frequently found in people diagnosed with a particular disease than in the general population. If you’ve read a news article about the “largest genetic study” of a disease like depression or Alzheimer’s disease, it was probably a genome-wide association study.
What motivated this research?
We wanted to come up with a better strategy for figuring out which genes were being implicated by genome-wide association studies. These studies tell you which genetic variants are implicated, not which genes. It’s not always clear which gene is being affected by a particular genetic variant, although often (maybe 60-70% of the time) it’s the gene in closest proximity to the genetic variant.
What was the most important finding of this study, in your opinion?
There are two findings we think are particularly important. First, we provide lists of candidate causal genes for major depression, bipolar disorder, and schizophrenia. By “causal”, we mean these genes are likely to be directly affected by the genetic variants from prior genome-wide association studies.
Second, we show that certain general properties of genes are highly predictive of whether they are causal for psychiatric disorders. These properties include: genes that are ‘loss-of-function intolerant’ (are disabled by mutations less than expected in the general population), genes that are specifically produced (‘expressed’) in the brain, and genes that cause neurodevelopmental disorders like autism and intellectual disability. We estimate these are all several times more likely to cause psychiatric disorders than other genes.
How does this change treatment in the future?
Our work gives researchers better tools for knowing which genes to study in the context of particular psychiatric disorders. Studying the right genes can help researchers find new drugs and treatments that target these genes.
Any next steps?
We are now asking which genetic variants are associated with other neuropsychiatric disorders, including dementia and neuropathic pain. We’re also interested in looking beyond the common ‘single-letter’ changes that genome-wide association studies focus on – we’re looking at rarer and more exotic forms of genetic variation, like when large parts of the genome are deleted or duplicated. We’re working with biologists to test how specific genetic variants impact the function of particular genes in brain cells.
What is the major take home message for the public?
The biology linking genetics to psychiatric disorders is complex but is slowly being unraveled through this effort and many others. We’ve discovered genetic variants and associated genes that may be playing an important role in contributing to major psychiatric disorders.
ImPACT Committee includes Krista Lanctôt, Alastair Flint, Meng-Chuan Lai and Simone Vigod.
Wainberg M, Merico D, Keller MC, Fauman EB, Tripathy SJ. Predicting causal genes from psychiatric genome-wide association studies using high-level etiological knowledge. Mol Psychiatry. 2022 Apr 11. doi: 10.1038/s41380-022-01542-6.