Atypical energy-related symptoms define biologically distinct subtypes of major depressive disorder

Major depressive disorder (MDD) is a complex psychiatric disorder, characterized by a range of mood, cognitive, and neurovegetative symptoms. Current diagnostic criteria treat opposite symptom directions as equivalent; weight gain or loss, and increased or decreased sleep, each count toward a single diagnosis. We defined three subgroups of individuals meeting criteria for MDD: AERS+ (hypersomnia with increased appetite/weight gain), AERS- (insomnia with appetite/weight loss), and an Uncategorized group, and conducted genome-wide association meta-analyses for each (Neff = 47,858, 156,624, and 215,828, respectively). We identified 27 genome-wide significant loci across subtypes, 4 for AERS+, 10 for AERS- and 13 for Uncategorized. AERS+ showed higher SNP-based heritability (10.9%) and lower polygenicity (1.7% of SNPs) than AERS- (7.9%; 2.9%) or Uncategorized (8.6%; 5.3%), with larger effect sizes at its associated loci. The AERS+ and AERS- subtypes were moderately genetically correlated (rg= 0.64, se = 0.04). Metabolic traits emerged as a primary differentiator: AERS+ correlated positively with BMI, metabolic syndrome, and related traits, whereas AERS- correlated weakly in the opposite direction. These findings show that the directionality of neurovegetative symptoms indexes genetic heterogeneity within MDD, with metabolic biology as a central axis of differentiation.