Recent research published in journals molecular psychiatry provide evidence that the genetic risk for major depression tends to be higher in people who develop a more severe form of the condition. By combining genetic data, self-reported symptom questionnaires, and long-term health records, researchers found that people who are genetically more likely to develop depression often report low self-esteem years before they require hospital treatment.
“Depression is a common disease in the population, but there is considerable individual variation in the presentation and course of symptoms. Current treatment guidelines are not differentiated enough to address this heterogeneity, and depression remains a major cause of disability worldwide,” said lead researcher Marit Hallam, a psychiatric specialist at Oslo University Hospital and associate professor at the University of Oslo.
“A potential future way to predict disease outcome and guide personalized treatment is to assess an individual’s genetic risk for depression (in terms of (a) polygenic risk score). Although this genetic discovery is not yet sufficient for clinical use, we had a unique data set that enabled new discoveries about the clinical potential of knowledge of genetic risk.”
A polygenic risk score is a number that summarizes an individual’s estimated genetic risk for a particular disease. This score is calculated by combining information from thousands of small genetic variations found throughout a person’s DNA code.
Scientists analyzed data from the Norwegian Mother and Child Cohort Study. This large-scale project included 105,623 participants, with an average age of approximately 34 years, and 58.5% of the group were women. Researchers tracked participants’ mental health over a 16-year follow-up period.
To understand each person’s genetic risk, the researchers calculated polygenic risk scores for major depression, bipolar disorder, and schizophrenia. They also calculated a genetic risk score for height, which serves as a comparison for physical characteristics. This allowed the team to verify that the mental health findings were specific to psychiatric genetic markers.
During the initial phase of the study, participants completed a self-report questionnaire regarding their mental health. These include the Symptom Checklist 5 to measure recent psychological distress and the Life Satisfaction Scale to measure general pessimism. Participants also completed the Rosenberg Self-Esteem Scale to assess their feelings of worthlessness.
The researchers then linked these survey responses with official medical records from the Norwegian Health Register from 2006 to 2022. They categorized the clinical data based on the severity of the depression and the type of medical care the person received. Categories include general primary care visits, specialty outpatient visits, and hospitalizations.
The analysis revealed that 31.1 percent of people had a diagnosis of depression on the spectrum during the 16-year follow-up period. This high rate partly reflects the inclusion of milder cases, such as those who visit their general practitioner because they feel slightly depressed. Across this broad spectrum, scientists have found a clear gradient linking genetic risk and depression severity.
People with high polygenic risk scores for major depression were more likely to be diagnosed with depression in a clinical setting. This genetic link became even stronger as the severity of the clinical diagnosis increased. The highest genetic risk was found in patients who ended up requiring inpatient treatment for depression.
Self-report questionnaires showed that higher genetic risk for major depression was associated with higher levels of distress, lower life satisfaction, and lower self-esteem. The association with low self-esteem was particularly strong for those who later required hospitalization. These survey responses were often recorded long before a formal clinical diagnosis appeared in the registry.
“Our findings indicate that people who develop more severe depression carry a greater genetic burden, which influences their responses on self-report measures in a different time frame than their registered depression,” Hallam told SciPost. “This association is very interesting because most of the survey data was collected before the diagnostic data from the registry.”
“A stronger association between genetic risk for depression and lower self-esteem in depressed patients with a history of inpatient treatment was not found in a subsample that excluded people with severe mental disorders,” she added. “This may indicate that genetic risk for depression shows the strongest predictive potential in the population of individuals who develop severe mental disorders.”
“I think it’s interesting to know that genetic risk can be linked to measurements from questionnaires, but in different ways depending on the severity of depression a case develops. Depression is a very complex and heterogeneous disease, so I’m surprised at the ‘knowledge’ that lies within genetic information.” ”
This pattern was specific to genetic risk for major depression. Genetic risk scores for bipolar disorder and schizophrenia did not show similar strong relationships with these self-report measures of depression. Height genetic score showed a slightly negative association with depression. That is, a genetic tendency to be taller was associated with slightly fewer diagnoses of depression.
Although this study provides new insights, there are some limitations and potential misconceptions to keep in mind. Readers should not assume that doctors can currently use genetic risk scores to fully predict a person’s mental health future. The researchers note that the polygenic risk score is still experimental and not yet powerful enough for clinical use alone.
Additionally, this study relies on medical registry data that first became fully available in 2008. Some participants may have had undocumented depressive episodes prior to this period, which could introduce a subtle bias in how cases were classified. Participants in cohort studies also tend to have a slightly higher socio-economic status than the general population.
Because genetic markers of height are often associated with high socio-economic status, this demographic bias may have influenced the comparative data for physical characteristics. Future research will need to refine how genetic risk scores are calculated to see if they can ultimately be integrated into practical clinical models.
“We cannot yet say that genetic risk is ready for clinical use,” Hallam said. “However, our proof-of-principle results indicate that further development of a polygenic score for major depression in current clinical use cases is worth pursuing.”
The study, “Associating polygenic risk scores with major depression and depression severity: 16-year follow-up of 105,623 people,” was authored by Marit Haram, Andreas Jangmo, Piotr Jaholkowski, Joëlle Pasman, Joeri Meijsen, John R. Shorter, Elizabeth C. Corfield, Oleksandr Frei, and Ted. Reichborn-Kenneld, Alphonso Bill, Yi Lu, Thomas Werge, Patrick Sullivan, Ole A. Andreassen, Martin Tesli.
