A new study is providing a clearer picture of the genetic landscape of major depression, revealing that the disorder may have fundamentally different biological roots depending on the age at which it first appears. The research, published in Nature Genetics, found that depression beginning in adolescence or young adulthood has a stronger genetic basis, is linked to early brain development, and carries a much higher genetic association with suicide attempts compared to depression that starts later in life.
Major depressive disorder is recognized as a clinically diverse condition, meaning its symptoms and course can vary substantially from person to person. Researchers have long suspected that this clinical variability might stem from different underlying causes.
One of the most apparent distinctions among individuals with depression is their age at onset. Depression that emerges early in life is often associated with more severe outcomes, including suicidal behavior, while late-onset depression has been linked more frequently to cognitive decline and cardiovascular problems.
To investigate whether these distinctions have a genetic basis, an international team of scientists from the Nordic TRYGGVE collaboration conducted a large-scale genetic study. The group leveraged the unique resources available in five Nordic countries: Denmark, Estonia, Finland, Norway, and Sweden.
These countries maintain comprehensive national health registries that track medical diagnoses over a person’s lifetime, allowing for a more objective way to determine the age of a first diagnosis, which serves as a reliable proxy for age of onset. This approach helped the researchers overcome challenges that have limited previous studies, such as reliance on patient memory and smaller sample sizes.
The researchers analyzed anonymized genetic and health data from over 150,000 individuals diagnosed with depression and more than 360,000 people without a diagnosis. They divided the depression cases into two groups: an early-onset group, with a first diagnosis at or before age 25, and a late-onset group, with a first diagnosis at or after age 50. Using a technique known as a genome-wide association study, they scanned the DNA of all participants, looking for small genetic variations that were more common in one of the depression groups compared to the control group.
The analysis identified twelve distinct regions of the genome associated with early-onset depression and two regions associated with the late-onset form. A closer examination of the genes located in these regions provided clues about their biological function. For the early-onset group, four of the identified genes are known to play roles in neurodevelopment and the formation of connections between brain cells.
To explore this further, the team analyzed whether the genetic signals for each depression subtype were concentrated in specific types of human tissue. The genetic markers for early-onset depression were significantly enriched in tissues from the fetal brain, but not in adult brain tissues. This finding suggests that the genetic risk for this form of depression may influence how the brain is constructed early in development.
The study also quantified the extent to which common genetic variants contribute to the risk for each subtype. This measure, known as heritability, was estimated to be 11.2 percent for early-onset depression. This figure was nearly double the heritability for late-onset depression, which was estimated at 6 percent. The results indicate that inherited genetic factors play a substantially larger role in the development of depression in younger individuals compared to those who experience their first episode later in life.
Next, the researchers explored the genetic overlap between the two depression subtypes and other health conditions. They found that while the two forms of depression shared a moderate genetic link with each other, they had very different relationships with other psychiatric disorders. Early-onset depression showed a particularly strong genetic correlation with suicide attempt; the shared genetic basis was more than twice as strong as the correlation between late-onset depression and suicide attempt.
Advanced statistical modeling suggested that this link to suicide risk is primarily a feature of the early-onset form. When the model accounted for the shared genetics between the two subtypes, the association between late-onset depression and suicide attempt was greatly diminished.
To investigate potential causal relationships, the team employed a method called Mendelian randomization. This technique uses genetic variants as a proxy for a risk factor to assess its effect on an outcome. The results suggested that a genetic predisposition to early-onset depression may have a causal influence on the risk of a suicide attempt. This effect was significantly larger than the one observed for late-onset depression.
The scientists also calculated polygenic risk scores for each individual. These scores summarize a person’s inherited predisposition for a condition based on thousands or millions of genetic markers. They found that the polygenic risk score for early-onset depression was a stronger predictor of severe clinical outcomes, such as hospitalization and later diagnosis of bipolar disorder or schizophrenia, compared to the risk score for late-onset depression.
“We show that early-onset depression has partly different genetic causes than depression that affects older individuals and that the risk of suicide attempts is increased,” said Yi Lu, a senior researcher at the Karolinska Institutet’s Department of Medical Epidemiology and Biostatistics and one of the study’s corresponding authors. “This is an important step towards precision medicine in psychiatry, where treatment and preventive measures are tailored to each individual.”
To understand the real-world implications, the researchers used the polygenic risk score for early-onset depression to stratify individuals based on their genetic risk for suicide attempt. Among people diagnosed with early-onset depression, those in the top 10 percent for genetic risk had a 26 percent cumulative incidence of a suicide attempt within ten years of their initial diagnosis. In contrast, those in the bottom 10 percent for genetic risk had a cumulative incidence of 12 percent over the same period.
“We hope that genetic information will be able to help healthcare professionals identify people at high risk of suicide, who may need more support and closer follow-up,” Lu said.
The study has some limitations. The analysis was conducted on individuals of European ancestry, and further research will be needed to see if these findings apply to more diverse populations. The researchers also note that their approach could be extended to explore the genetic architecture of other clinical features of depression, such as psychotic symptoms or the level of disability. The team plans to investigate how the identified genetic differences relate to brain development, stress, and life experiences.
The study, “Genome-wide association analyses identify distinct genetic architectures for early-onset and late-onset depression,” was authored by John R. Shorter, Joëlle A. Pasman, Siim Kurvits, Andreas Jangmo, Joonas Naamanka, Arvid Harder, Espen Hagen, Kaarina Kowalec, Nelli Frilander, Richard Zetterberg, Joeri J. Meijsen, Jesper R. Gådin, Jacob Bergstedt, Ying Xiong, Sara Hägg, Mikael Landén, Christian Rück, John Wallert, Alkistis Skalkidou, Elise Koch, Bayram C. Akdeniz, Oleksandr Frei, FinnGen, Iiris Hovatta, Ted Reichborn-Kjennerud, Thomas M. Werge, Patrick F. Sullivan, Ole A. Andreassen, Martin Tesli, Kelli Lehto, Alfonso Buil & Yi Lu.
