A groundbreaking study published in Nature Genetics is shedding new light on the genetic underpinnings of major depressive disorder, suggesting that its biological roots differ significantly depending on the age of onset. The research indicates that depression beginning in adolescence or early adulthood has a stronger genetic basis and is more closely associated with early brain development, as well as a higher genetic link to suicide attempts, compared to depression that manifests later in life.
Major depressive disorder is known for its clinical diversity, with symptoms and progression varying widely among individuals. Researchers have long hypothesized that this variability might be due to different underlying causes. One of the most notable differences among those with depression is the age at which it first occurs. Early-onset depression is often linked with more severe outcomes, including suicidal behavior, while late-onset depression is more frequently associated with cognitive decline and cardiovascular issues.
Genetic Foundations of Depression
To explore these distinctions, an international team from the Nordic TRYGGVE collaboration conducted an extensive genetic study. Utilizing resources from Denmark, Estonia, Finland, Norway, and Sweden, where comprehensive national health registries track medical diagnoses over a lifetime, the researchers were able to objectively determine the age of first diagnosis as a proxy for age of onset. This method helped overcome limitations of previous studies, such as reliance on patient memory and smaller sample sizes.
The study analyzed genetic and health data from over 150,000 individuals diagnosed with depression and more than 360,000 without a diagnosis. Participants were divided into two groups: early-onset, with a first diagnosis at or before age 25, and late-onset, with a first diagnosis at or after age 50. Using genome-wide association studies, the team scanned DNA for genetic variations more common in one depression group compared to the control group.
The analysis identified twelve distinct genomic regions associated with early-onset depression and two regions linked to late-onset depression.
Biological Implications and Heritability
Further examination of genes in these regions revealed insights into their biological functions. For early-onset depression, four genes were identified as playing roles in neurodevelopment and brain cell connectivity. The genetic markers for early-onset depression were significantly enriched in fetal brain tissues, suggesting that genetic risk may influence brain construction early in development.
The study also quantified the heritability of each depression subtype. Heritability for early-onset depression was estimated at 11.2 percent, nearly double that of late-onset depression, which was 6 percent. This indicates a larger role for inherited genetic factors in younger individuals experiencing depression.
Genetic Overlap with Other Disorders
The researchers examined the genetic overlap between depression subtypes and other health conditions. While both forms of depression shared a moderate genetic link, they had different relationships with other psychiatric disorders. Early-onset depression showed a strong genetic correlation with suicide attempts, with a shared genetic basis more than twice as strong as that 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 Karolinska Institutet.
Real-World Implications and Future Research
To understand the practical implications, researchers used polygenic risk scores to stratify individuals by genetic risk for suicide attempts. Among those diagnosed with early-onset depression, individuals in the top 10 percent for genetic risk had a 26 percent cumulative incidence of a suicide attempt within ten years, compared to 12 percent for those in the bottom 10 percent.
“We hope that genetic information will help healthcare professionals identify people at high risk of suicide, who may need more support and closer follow-up,” Lu added.
Despite its significant findings, the study has limitations. It was conducted on individuals of European ancestry, necessitating further research to determine applicability across diverse populations. The team also plans to explore the genetic architecture of other depression features, such as psychotic symptoms or disability levels, and how these genetic differences relate to brain development, stress, and life experiences.
As the field of psychiatric genetics advances, this study represents a crucial step toward precision medicine in psychiatry, where treatments and preventive measures are increasingly tailored to individual genetic profiles.
