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

Background

Major Depressive Disorder (MDD) is heritable and polygenic, yet the relative diagnostic specificity, developmental impact, and cross-ancestry generalizability of MDD polygenic risk scores (MDD-PRS) remain unclear.

Methods

In two sites of the Brazilian High-Risk Cohort (N=2,163; ages 6-23; 45.6% female), we used a discovery-replication design to test associations between MDD-PRS and (i) lifetime DSM-IV diagnoses; (ii) longitudinal depressive-symptom trajectories from latent growth-curve models; and (iii) late-adolescent/young-adult depressive symptoms and nonsuicidal self-injury (NSSI). Analyses used weighted ordinary least squares and quantile regression, adjusting for age, sex, socioeconomic status, genetic principal components, and psychiatric comorbidity.

Results

MDD-PRS showed relative specificity for MDD in both sites, explaining approximately 2.6-3.6% of liability-scale variance; no other diagnostic category survived false-discovery-rate correction. Longitudinally, higher MDD-PRS predicted higher initial level (β=0.10-0.18; p<0.001 in both sites), faster rate of increase (β=0.07-0.10; p=0.004 and p<0.001), and higher time-averaged level (β=0.13-0.20; p<0.001 in both sites) of depressive symptoms, with effects strengthening at higher quantiles. Cross-sectionally, MDD-PRS were associated with more depressive symptoms (β=0.15-0.17; p<0.001 in both sites). For NSSI, a main-effect association was observed (β=0.09; p<0.001), but it remained significant only in a post-hoc MDD-PRS×lifetime-MDD interaction among individuals with MDD (β=0.24; p=0.014).

Conclusions

In this deeply phenotyped, admixed cohort, MDD-PRS showed relative diagnostic specificity and marked a more severe developmental course of depression, with NSSI associations contingent on MDD diagnosis, supporting the relative specificity, developmental utility, and cross-ancestry relevance of MDD-PRS.