Differentiation of early-onset and late-onset genetic depression

By separating early- and late-onset depression, researchers have uncovered hidden genetic signatures that are reshaping our understanding of risk, severity and brain development.

Study: Genome-wide association analyzes identify distinct genetic architectures for early- and late-onset depression. Image credit: Bits And Splits/Shutterstock.com

Major depressive disorder (MDD) presents with a wide range of clinical features, reflecting the interplay of genetic and environmental factors. A better understanding of its causes would promote improved clinical management and better outcomes, enabling targeted strategies.

A recent study published in the journal Genetics of Nature examined differences in genetic factors underpinning early- and late-onset MDD subtypes.

Defining subtypes of depression

Early-onset and late-onset MDD present and progress differently. The former is associated with psychotic symptoms, suicide attempts, and other physical and mental illnesses. In contrast, late-onset MDD tends to manifest with impaired cognitive performance and increased cardiovascular risk.

However, different methodologies, small samples, and recall bias, among other reasons, contribute to the challenge of distinguishing between early and late onset. The current study took advantage of large sample sizes and the availability of longitudinal data, including accurate records of patient age at first diagnosis, a valuable proxy for age of MDD onset.

The availability of large samples from the Psychiatric Genomics Consortium and other global biobanks has facilitated genome-wide association studies (GWAS) of MDD. While this approach has revealed genetic variants associated with MDD, the genetic loci associated with specific MDD subtypes remain unexplored.

How depression was analyzed

The current study conducted a GWAS-based meta-analysis of early- and late-onset MDD, thereby overcoming clinical heterogeneity. The study was based on Nordic biobanks providing longitudinal health data to investigate 46,708 cases of early-onset MDD and 37,168 cases of late-onset MDD.

Age at first diagnosis closely approximates true age of onset, with a reported genetic correlation of ∼0.95 between the two measures.

Basic genetic differences

The scientists discovered 12 genomic loci (chromosomal locations), comprising 17 significant genes associated with early-onset MDD, versus only two (including four significant genes) for late-onset MDD. These were among the 80 loci in the GWAS of all MDD cases and are in agreement with those reported in previous similar studies. The study also noted that SNP-based heritability was almost twice as high for early-onset (11.2%) than late-onset MDD (6%) and that early-onset MDD showed lower polygenicity, suggesting fewer causative variants with comparatively larger effect sizes.

Early- and late-onset MDD were moderately correlated with each other, indicating the existence of differences in their genetic profiles. Early onset MDD was linked to genetic loci important in neurodevelopment, suggesting a link to early brain development. In contrast, in late-onset MDD patients, only one epigenetic marker was present in male fetal tissues. Neither subtype showed enrichment in adult brain tissues, which the authors suggested may reflect limited statistical power, especially for late-onset MDD.

The two MDD subtypes also differed in the association between their genetic architecture and other characteristics. Early-onset MDD loci showed the highest association with suicide attempts, more than twice as high as those of late-onset MDD. Early onset MDD was more strongly associated with suicide attempts than the other subtype, but both had similar effects on suicide death.

Mendelian randomization analyzes further supported a potential causal effect of early-onset MDD on suicide attempt, while the effect on death by suicide was similar between subtypes.

The two subtypes also showed differences in their association with PTSD, childhood abuse, autism spectrum disorder, and schizophrenia, among others. Early onset MDD had overlapping genetic associations with markers of heart failure and body mass index.

Interestingly, late-onset MDD also showed an overlap of its genetic loci with several features such as suicide attempt or death by suicide. However, these appeared to be primarily driven by genes common to both subtypes and were attenuated after adjustment for early-onset MDD. Conversely, the reverse was not true. There was limited duplication of the subtype-specific loci in the UK Biobank, with only one locus showing nominal significance. However, effect sizes across cohorts remained highly correlated.

PRS risk standards

The researchers also calculated polygenic risk scores (PRS) for both MDD subtypes. They found significant associations between PRS for early-onset MDD with various clinical indicators and outcomes, including early-onset and lifetime risk of MDD, risk of hospitalization, and a change in diagnosis to bipolar disorder or schizophrenia over time.

A number of psychiatric conditions were uniquely associated with early onset MDD PRS, including suicide attempt or deliberate self-harm and problems related to childhood abuse. Additional unique associations included conduct disorder, schizotypal disorder, and other ICD-10 codes associated with childhood adversity. Late-onset MDD was more likely to be associated with mental or behavioral illness due to sedative or hypnotic use or obsessive-compulsive disorder.

The top tenth percentile of early-onset MDD PRS scores had a 26% risk of suicide attempts in the first ten years after MDD diagnosis. The middle 80% had a somewhat lower risk, at 20%, while the lowest tenth percentile had a 12% risk. The relative risk of suicide attempt was reduced by 43% in the lowest decile compared to the middle group, but the upper decile had a 13% higher risk than the middle.

The hazard curves for the middle and top deciles diverged only about 5.5 years after diagnosis, and the hazard ratio for the top decile was only marginally significant.

Specifically, youth are more likely to attempt suicide, making the early-onset MDD PRS potentially valuable for identifying high-risk youth in this subgroup.

Implications for psychiatry

The study focused on identifying genetic loci for specific MDD subgroups, defined by their signs and symptoms, thereby reducing unwanted genetic variation among MDD patients. Similar strategies could be applied to identify additional subgroups of MDD defined by features such as vegetative symptoms or psychotic manifestations.

Taken together, our findings can inform precision psychiatric approaches to MDD.

The authors further emphasized that stratifying MDD by age of onset may reveal more biologically coherent subtypes and could aid in the development of targeted risk prediction and prevention strategies.

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