Genetic risk for major depression linked to lower self-esteem years before severe diagnosis

A recent study published in the journal Molecular Psychiatry provides evidence that an individual’s genetic risk for major depression tends to be higher in those who develop more severe forms of the condition. By combining genetic data, self-reported symptom questionnaires, and long-term health records, researchers found that people with a higher genetic likelihood of depression often reported lower self-esteem years before needing hospital treatment.

“Depressive disorders are common in the population, but the symptom expression and course of the disorders vary quite a bit between individuals. The current treatment guidelines are not differentiated enough to address this heterogeneity, and depression is still a major cause of disability worldwide,” said lead researcher Marit Haram, a specialist in psychiatry at Oslo University Hospital and an associate professor at the University of Oslo.

“A potential future method to predict illness outcome and guide personalized treatment is to assess the individual genetic risk for depression (in terms of [a] polygenic risk score). The genetic discovery is not yet good enough for clinical use, but we had a unique dataset that made it possible to make new discoveries of the clinical potential that lies in the knowledge of genetic risk.”

A polygenic risk score is a number that summarizes a person’s estimated genetic risk for a specific disease. This score is calculated by combining information from thousands of tiny genetic variants found across a person’s entire DNA code.

The scientists analyzed data from the Norwegian Mother, Father and Child Cohort Study. This large project included 105,623 participants, with an average age of about 34 years, and 58.5 percent of the group was female. The researchers tracked the participants’ mental health over a 16-year follow-up period.

To understand each person’s genetic risk, the team calculated polygenic risk scores for major depression, bipolar disorder, and schizophrenia. They also calculated a genetic risk score for height to serve as a physical trait comparison. This allowed the team to verify that the mental health findings were specific to psychiatric genetic markers.

Early in the study, participants completed self-report questionnaires about their mental well-being. These included the Symptom Checklist-5 to measure recent emotional distress, and the Satisfaction With Life Scale to gauge general pessimism. Participants also completed the Rosenberg Self-Esteem Scale to assess internal feelings of unworthiness.

The researchers then linked these survey answers to official medical records from Norwegian health registries between 2006 and 2022. They categorized the clinical data based on how severe the depression was and what kind of medical care the person received. The categories included general primary care visits, outpatient specialist visits, and inpatient hospital stays.

The analysis revealed that 31.1 percent of the individuals received a diagnosis on the depression spectrum during the 16 years of tracking. This high percentage partly reflects the inclusion of mild cases, such as general practitioner visits for feeling a bit down. Across this wide spectrum, the scientists found a clear gradient connecting genetic risk and the severity of depression.

Individuals with higher polygenic risk scores for major depression were more likely to be diagnosed with depression in a clinical setting. This genetic link grew stronger as the severity of the clinical diagnosis increased. The highest genetic risk was seen in patients who eventually required inpatient hospital care for their depression.

When looking at the self-reported questionnaires, higher genetic risk for major depression was linked to higher levels of distress, lower satisfaction with life, and lower self-esteem. The link to low self-esteem was particularly strong in individuals who later required inpatient hospitalization. These survey responses were often recorded long before the official clinical diagnoses appeared in the registries.

“The finding illustrates that individuals who developed more severe depression carry a greater genetic burden, which influences their answers on self-report measures in a different timeframe than the registered depression,” Haram told PsyPost. “The data from the questionnaires were mostly collected before the diagnostic data from the registries, so this association is quite interesting.”

“The stronger associations between genetic risk for depression and lower self-esteem in depression cases with a history of inpatient care were not found in a sub-sample that excluded individuals with severe mental disorders,” she added. “This could indicate that the genetic risk for depression shows the strongest predictive potential in populations of individuals who will develop severe mental disorders.”

“I find it interesting to see that genetic risk could be associated with measures from questionnaires, but in a different way depending on the severity of depression that cases developed. Depression is a very complex and heterogeneous illness, so I am surprised by the ‘knowledge’ that lies in the genetic code.”

This pattern was specific to the genetic risk for major depression. The genetic risk scores for bipolar disorder and schizophrenia did not show the same strong relationships with these self-reported depression measures. The genetic score for height showed a slight negative relationship with depression, meaning taller genetic tendencies were linked to slightly fewer depression diagnoses.

While the study provides new insights, there are a few limitations and potential misinterpretations to keep in mind. Readers should not assume that a genetic risk score can currently be used by a doctor to perfectly predict a person’s mental health future. The researchers note that polygenic risk scores are still in an experimental phase and are not yet powerful enough for standalone clinical use.

Additionally, the study relies on medical registry data that was only fully available starting in 2008. Some participants might have had unrecorded depressive episodes before this period, which could subtly bias how cases were categorized. The participants in the cohort study also tend to have a slightly higher socioeconomic status than the general population.

Because genetic markers for height are often linked to higher socioeconomic status, this demographic skew might have influenced the physical trait comparison data. Future research will need to refine how genetic risk scores are calculated to see if they can eventually be integrated into practical clinical models.

“We cannot say that the genetic risk is ready for use in the clinical context yet,” Haram said. “But our proof-of-principle results show that further development of polygenic scores for major depression for the current clinical use case is worth pursuing.”

The study, “Associations of polygenic risk scores for major depression and depression severity: an investigation of 105 623 individuals with 16 years follow-up,” was authored by Marit Haram, Andreas Jangmo, Piotr Jaholkowski, Joëlle Pasman, Joeri Meijsen, John R. Shorter, Elizabeth C. Corfield, Oleksandr Frei, Ted Reichborn-Kjennerud, Alfonso Buil, Yi Lu, Thomas Werge, Patrick Sullivan, Ole A. Andreassen, and Martin Tesli.