Polygenic Risk for Major Depression: Diagnostic Specificity and Developmental Trajectories in an Admixed Youth Cohort

Area of Science:

• Psychiatry
• Genetics
• Epidemiology

Background:

• Major Depressive Disorder (MDD) is a heritable, polygenic condition.
• The diagnostic specificity, developmental impact, and generalizability of MDD polygenic risk scores (MDD-PRS) across diverse ancestries are not well understood.

Purpose of the Study:

• To investigate the diagnostic specificity of MDD-PRS for Major Depressive Disorder.
• To examine the association of MDD-PRS with longitudinal depressive symptom trajectories and late-adolescent/young-adult outcomes, including nonsuicidal self-injury (NSSI).
• To assess the cross-ancestry relevance and developmental utility of MDD-PRS in an admixed population.

Main Methods:

• Utilized a discovery-replication design in the Brazilian High-Risk Cohort (N=2,163; ages 6-23).
• Tested associations between MDD-PRS and lifetime DSM-IV diagnoses, longitudinal depressive symptom trajectories (latent growth-curve models), and adolescent/young-adult depressive symptoms and NSSI.
• Employed weighted ordinary least squares and quantile regression, adjusting for covariates.

Main Results:

• MDD-PRS demonstrated relative specificity for MDD, explaining 2.6-3.6% of liability variance; no other diagnoses met significance thresholds.
• Higher MDD-PRS predicted increased initial levels, faster rates of increase, and higher time-averaged levels of depressive symptoms longitudinally.
• MDD-PRS were associated with depressive symptoms cross-sectionally, and with NSSI, particularly among individuals with MDD.

Conclusions:

• MDD-PRS exhibit relative diagnostic specificity for Major Depressive Disorder.
• MDD-PRS are associated with a more severe developmental course of depression.
• The findings support the utility and cross-ancestry relevance of MDD-PRS in understanding depression.