Melancholic features and typical neurovegetative symptoms of major depressive disorder show specific polygenic patterns

Major depressive disorder (MDD) is a highly prevalent psychiatric condition characterised by a heterogeneous clinical presentation and an estimated twin-based heritability of ~40-50 %. Different clinical MDD subtypes might partly reflect distinctive underlying genetics. This study aims to investigate if polygenic risk scores (PRSs) for different psychiatric disorders, personality traits, and substance use-related traits may be associated with different clinical subtypes of MDD (i.e., MDD with melancholic or psychotic features), higher symptom severity, or different clusters of depressive symptoms (i.e., sadness symptoms, typical neurovegetative symptoms, detachment symptoms, and negative thoughts).The target sample included 1149 patients with MDD, recruited by the European Group for the Study of Resistant Depression. PRSs for 25 psychiatric disorders and traits were computed based on the most recent publicly available summary statistics of the largest genome-wide association studies. PRSs were then used as predictors in regression models, adjusting for age, sex, population stratification, and recruitment sites.Patients with MDD having higher PRS for MDD and loneliness were more likely to exhibit melancholic features of MDD (p = 0.0009 and p = 0.005, respectively). Moreover, patients with higher PRS for alcohol intake and post-traumatic stress disorder were more likely to experience greater typical neurovegetative symptoms (p = 0.0012 and p = 0.0045, respectively).The proportion of phenotypic variance explained by the PRSs was limited.This study suggests that melancholic features and typical neurovegetative symptoms of MDD may show distinctive underlying genetics. Our findings provide a new contribution to the understanding of the genetic heterogeneity of MDD.