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Genetic Susceptibility to Major Depressive Disorder Associates with Symptom Trajectories Across Childhood

Key findings

  • This study examined associations of a polygenic risk score with depressive symptom trajectories across a 13-year age range in children and adolescents
  • Three time-dependent measures (class, onset and cumulative symptom burden) showed that polygenic influences may shape depressive symptom trajectories across child development
  • Increased genetic risk of depression manifested as elevated depressive symptoms during late childhood to early adolescence (approximately ages 10–15)
  • No gene reached statistical significance at the genome-wide level, but seven genes were nominally associated with depressive symptom features and two were nominally associated with onset and cumulative burden of depressive symptoms

Individuals with major depressive disorder are different ages at first onset and show different patterns of persistence once the disorder begins. Genetic mechanisms may explain part of this heterogeneity, and polygenic risk scores (PRSs) have been used to assess the impact of genetic contributions on subtypes of depression. PRSs integrate information from many common DNA variants into a single measure of inherited susceptibility.

Alexandre A. Lussier, PhD, research fellow, and Erin C. Dunn, ScD, MPH, of the Psychiatric and Neurodevelopmental Genetics Unit at Massachusetts General Hospital, and colleagues recently examined the genetic contributions to depressive symptoms in youths four to 16.5 years old, the longest interval ever examined for pediatric depressive symptoms. In The Journal of Child Psychology and Psychiatry, they report that a PRS captured genetic risk of depression across this age span.

Study Cohort

Data for the analysis came from 7,308 children in the Avon Longitudinal Study of Parents and Children, a prospective, population-based cohort, who had genotype data available and had at least one measure of depressive symptoms completed by a caregiver between four and 16.5 years of age.

Study Methods

Ina previous study, posted on the MedRxiv preprint server, researchers at Mass General and elsewhere introduced a new technique called growth mixture modeling with structured residuals, which enables assessment of individual differences in the course of depression. In the current study, the researchers used this method to identify six classes of depressive symptom trajectories in the 7,308 youths:

  • Minimal symptoms (stable and low levels of symptoms across time)—50%
  • Adolescent spike (low childhood level of symptoms spiking to high levels in adolescence)—3%
  • Late childhood peak (symptoms increasing through middle childhood and decreasing during adolescence)—3%
  • Childhood decrease (high level of symptoms decreasing during childhood)—7%
  • High/reversing (high level of symptoms with sharp oscillations between ages)—9%
  • High/renitent (high level of symptoms with few oscillations between ages)—28%

Besides symptom trajectories, the team studied two other outcome measures:

  • The level of depressive symptoms at age four (the earliest age of depression onset reported in previous studies)
  • The cumulative level of depressive symptoms

The researchers tested whether these three measures were associated with a PRS they constructed using statistics from three large-scale genome-wide association studies of depression. They then performed the first genome-wide, gene-level analysis to determine whether specific genes were associated with the outcome measures.

PRS and Depression Trajectories

Each one standard deviation increase in PRS was associated with increased odds of assignment to:

  • The late childhood peak class, high/reversing class or high/renitent class compared with the minimal symptoms class
  • The high/renitent class compared with the childhood decrease class

Symptoms linked to genetic liability for depression were more likely to emerge during late childhood to early adolescence (approximately ages 10–15).

PRS and Symptom Onset, Cumulative Burden

A higher PRS was associated with a higher level of depressive symptoms at age four and a higher cumulative burden of depressive symptoms.

Gene-Level Analyses

No gene reached statistical significance at the genome-wide level when subjects in the high/renitent class were compared with those in the minimal symptoms class or when onset and cumulative symptom burden were analyzed.

However, seven genes were nominally associated with depressive symptom features. Two of the same genes were nominally associated with both onset and cumulative burden of depressive symptoms.

Looking Ahead

These findings suggest how polygenic influences may shape depressive symptom trajectories. It may ultimately be possible to identify genetic factors that shape the age of depression onset and overall disease course, providing early targets for therapies that prevent depression.

Learn more about Dr. Dunn's research

Learn more about the Psychiatric & Neurodevelopmental Genetics Unit

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