New hope for early detection and mitigation of serious mental illness

June 6, 2023

Dr. Rudolf Uher, the senior supervisor for the recently published study on genetic testing for neuroticism with Dr. Alyson Zwicker, the study’s lead investigator.

New international research, based in Halifax, shows genetic testing for neuroticism is now nearly as reliable as full family history for pinpointing the young people likely to develop severe mental illness.

The study, supported by Genome Atlantic and recently published in the American Journal of Psychiatry, suggests a combination of family history and genetic testing for neuroticism could significantly improve the early detection of youth at risk of developing serious mental conditions such as depression, bipolar disorder and psychosis. Once identified, the individuals could be flagged for early intervention or preventive treatment.

“This is a huge step towards making psychiatric genetics useful”

- Dr. Rudolf Uher

“This is a huge step towards making psychiatric genetics useful” is how Dr. Rudolf Uher, the senior supervisor for the study and the Canadian Chair in Early Interventions in Psychiatry at Dalhousie University, described this latest genetic discovery.

“This is critically important research”, agreed Steve Armstrong, Genome Atlantic’s president and CEO. “It opens up major possibilities to help a great many people around the world. It could eventually reduce their chances of developing serious mental illness and spare their families and friends years of distress. We are very proud of our funding role in this project.”

Although it has been known for many years that mental illness runs in families, complete family medical histories are often difficult or impossible to obtain. Adoptions, separations and surrogacy are just some of the features of contemporary family life that compound the difficulty. Meanwhile, tracking down the genes responsible for mental illness is an ongoing challenge.

“Finding the genetic variants for a disorder is difficult, because there are so many genetic variants, said Dr. Uher. “There are millions of them in the human genome.” Comparing people with and without a disorder and testing all the variants in case control studies is a complex, painstaking process yielding varying results.

This latest study sidestepped some of the drawbacks by taking advantage of existing genome-wide association studies. The research team of Drs. Uher and Alyson Zwicker, a third-year Dalhousie University medical student and the lead investigator for the study, put all the genetic variants together and calculated the polygenic scores of 1,884 young people in eight international studies in seven countries. Of that group, 1,339 individuals were known to have parents with mood or psychotic disorders.

We are predicting because we want to prevent, and we only communicate the information about the risk if we have something to offer to mitigate it.

- Dr. Rudolf Uher

Polygenic scores reflect an aggregate of risk conferred by an individual’s genetic variants that assess the possibility of developing a particular condition later in life. Blood and saliva samples were used in this study to test for these genetic variants in the participants.

The researchers found that while polygenic scores work about two-thirds as well as complete family histories do in identifying young persons predisposed to developing severe mental illness, they made an unexpected discovery when they took a closer look at the scores for neuroticism.

They found the scores for that condition, a common one with minor symptoms such as over sensitivity and undue worry, did almost as well as family history at identifying the young people at risk of developing a major mental illness. “The beauty of neuroticism is that it actually adds to the family history; it helps us predict better even for people whose family history we know” explained Dr.Uher. The findings are entirely new.

“I’ll tell you why I’m excited about this, “ he said. “The power of the genetic predictions keeps increasing in a predictable way with the size of the discovery in genome-wide association studies.”

He believes the reason why the polygenic score for neuroticism proved to be such a powerful predictor is because it is based on a “very large genome-wide association study,” compared to scores for other conditions such as schizophrenia, bipolar disorder, depression and the rest.

So, while the polygenic score for neuroticism is now nearly a match for family history, as the scores are refined using larger sample sizes in bigger genome-wide association studies, he said “it probably means we will match family history within the next five years and we may actually surpass it in the next decade.”

The most recent genome-wide association study, for example, focused on bipolar disorder. Forty thousand people with the condition were involved, yielding slightly more than 60 genetic variants associated with the disorder although the true number is estimated to be several thousand. “So there’s still more to be confirmed or discovered for sure than what we have now,” he said. By comparison, the polygenic score for neuroticism is based on more than 200,000 people.

The new published study involved nearly 2,000 offspring of individuals with bipolar disorder as well as a control group and children of parents with other mental illness. Putting together such a large sample was “the biggest feat,” said Dr. Uher, “and that was the nice thing of bringing together eight groups across the world.” It now offers significant follow up potential for tracking the participants long-term to test the accuracy of polygenic scores or any other predictor.

He stressed that a genetic predisposition to mental illness does not seal an individual’s fate. “We are predicting because we want to prevent, and we only communicate the information about the risk if we have something to offer to mitigate it.”

Modifying the risk through early intervention is now where Drs. Uher and Zwicker want to focus the next phase of their research. A formidable team, they have now published at least 21 papers together.This latest research was supported by Genome Atlantic via Genome Canada’s Regional Priorities Partnership Program (RP3), with added help from the Canada Research Chairs Program, Canadian Institutes of Health Research (CIHR), Research Nova Scotia, the Nova Scotia Health, the Dalhousie University Department of Psychiatry, and the former Dalhousie Medical Research Foundation.

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