Summary: Polygenic risk scores derived from large adult studies can identify children and adolescents at increased risk of developing depression, predict likely severity and age of onset, and provide insight for targeted prevention—especially when combined with information about childhood abuse.

Source: Max Planck Institute

Genetic Score Predicts Depression Risk and Severity in Youth

An international research team led by Munich-based investigators at the Max Planck Institute of Psychiatry and LMU Medical Center, in collaboration with researchers from Emory University (USA), the University of Coimbra (Portugal) and the University of Helsinki (Finland), has demonstrated that a genetic risk score calculated from adult data can predict depression outcomes in children and adolescents. The score not only identified youths more likely to develop depression, but also related to symptom severity and earlier age of onset. The researchers observed an additive effect when youth with high genetic risk had experienced childhood abuse.

Depression is the leading cause of disability worldwide, affecting more than 300 million people. It results from a complex interplay of biological, psychological and social factors and frequently first appears during adolescence. Detecting risk factors before clinical symptoms emerge is critical for effective preventive strategies that can reduce long-term burden.

What the Study Tested

The team asked whether polygenic risk scores (PRSs) for a broad depression phenotype—derived from a large genome‑wide association study (GWAS) in adults—could predict clinically relevant depression outcomes in youth. Unlike traditional genetic studies that examine single genetic variants one at a time, a PRS aggregates the influence of many variants across the genome. Individual variants each exert only a small effect on risk, but combined they can reveal hidden vulnerability and offer a clearer signal of genetic liability. This approach has been applied to other common conditions such as cardiovascular disease and diabetes.

First author Thorhildur Halldorsdottir explains the approach: the PRS was built from genetic summary statistics obtained from a very large adult sample with depression and then applied to several smaller youth cohorts to test whether it predicted clinical depression, depressive symptoms and age at onset. The study also evaluated the contribution of childhood abuse, a well-established environmental risk factor for later depression.

Halldorsdottir: “We found that both the polygenic risk score and exposure to childhood abuse provided useful information for identifying youth likely to develop depression.”

Key Findings

Elisabeth Binder, director of the department where the research was conducted, highlights the significance: “This is the first study to show that a polygenic risk score calculated from adults with depression can identify children at elevated risk before clinical symptoms appear.”

The study analyzed multiple cohorts that were genome‑wide genotyped and had measures of major depression, depressive symptoms and childhood abuse:

• A clinical cohort of 279 youths diagnosed with major depression (mean age 14.8 years, 68% female) and 187 healthy controls (mean age 14.7 years, 63% female).
• An epidemiological cohort of 1,450 adolescents (mean age 14.0 years, 63% female), including 694 participants who were not clinically depressed at baseline and were followed up at 6, 12 and 24 months.
• A replication epidemiological cohort assessed at ages 8 (N=184) and 11 (N=317) years.

Major results included:

• In the clinical cohort, the depression PRS predicted case versus control status (odds ratio = 1.56), greater depression severity, and younger age at onset.
• In the first epidemiological cohort, the PRS predicted baseline depressive symptoms and prospectively predicted the onset of moderate to severe symptoms (hazard ratio = 1.20).
• Associations with depressive symptoms were replicated in the second epidemiological cohort.
• The PRS and childhood abuse had additive effects on depression outcomes, meaning each contributed independently to risk; however, no significant statistical interaction between PRS and abuse was found.

Implications for Prevention and Care

Effective psychological and pharmacological treatments for depression are well established, and combined approaches often yield the best outcomes. However, broad implementation of early interventions in public health is constrained by limited resources. Gerd Schulte‑Körne, Director and Chair of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy at LMU University Hospital and co‑investigator on the study, suggests that genetic risk information could help prioritize scarce resources: “In the future, findings like these could guide targeted prevention for youths at greatest risk—those with high polygenic risk scores and/or a history of childhood abuse—so that interventions reach those most likely to benefit.”

Binder adds a note of caution and opportunity: “More work is needed to refine early identification of at‑risk youth. Still, being able to identify children who are more likely to develop depression would create opportunities to implement effective prevention and reduce the disorder’s substantial burden.”

Source:
Max Planck Institute

Media contact:
Anke Schlee – Max Planck Institute

Image source:
The image is in the public domain.

Original Research: Closed access
Thorhildur Halldorsdottir, Charlotte Piechaczek, Ana Paula Soares de Matos, Darina Czamara, Verena Pehl, Petra Wagenbuechler, Lisa Feldmann, Peggy Quickenstedt‑Reinhardt, Antje‑Kathrin Allgaier, Franz Joseph Freisleder, Ellen Greimel, Tuomas Kvist, Jari Lahti, Katri Räikkönen, Monika Rex‑Haffner, Eiríkur Örn Arnarson, W. Edward Craighead, Gerd Schulte‑Körne, Elisabeth B. Binder.
Article: “Polygenic Risk: Predicting Depression Outcomes in Clinical and Epidemiological Cohorts of Youth.” American Journal of Psychiatry. DOI: 10.1176/appi.ajp.2019.18091014

Abstract (Condensed)

Objective: To determine whether polygenic risk scores for a broad adult depression phenotype predict major depression and depressive symptoms in youth and whether they interact with childhood abuse.

Methods: Clinical and epidemiological youth cohorts (totaling several thousand participants across discovery and replication samples) were genome‑wide genotyped and assessed for depression and childhood abuse. PRSs were calculated from the largest GWAS on depression available and tested for associations with depression outcomes.

Results: Depression PRSs calculated from adult data generalized to youth: they predicted case status, symptom severity and earlier age at onset in a clinical sample, predicted baseline depressive symptoms and future onset of moderate to severe symptoms in an epidemiological cohort, and these symptom associations were replicated. PRS and childhood abuse contributed additively to risk.

Conclusions: Polygenic risk scores derived from adults can serve as early indicators of clinically significant depression in children and adolescents and may help guide targeted prevention strategies.