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

Authors

Marcelo José Abduch Adas Brañas, Lucas Toshio Ito, Marcos Signoretti Croci, Ana Beatriz Ravagnani Salto, Victoria Fogaça Doretto, Marcos Leite Santoro, Vanessa Kiyomi Ota, Luis Augusto Rohde, Giovanni Abrahão Salum, Lois W Choi-Kain, Síntia Belangero, Euripedes Constantino Miguel, Maurício Scopel Hoffmann, Pedro Mario Pan

Published in

Biological psychiatry. Jul 17, 2026. Epub Jul 17, 2026.

Abstract

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.
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.
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).
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.

PMID:
42462945
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.

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