medRxiv : the preprint server for health sciences · 2026
Atypical energy-related symptoms define biologically distinct subtypes of major depressive disorder.
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Harder Arvid, Wang Rujia, Bergstedt Jacob, Huider Floris, Kurvits Siim, Thorp Jackson, Gong Tong, Assary Elham, Thijssen Anaïs B, Merola Giuseppe Pierpaolo, Goula Anastasia A, Bentwood Sam, Karlsson Robert, Pasman Joelle A, Fabbri Chiara, Hickie Ian B, Peyrot Wouter J, Levinson Douglas F, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Potash James B, Shi Jianxin, Medland Sarah E, Mitchell Brittany L, Kwong Alex S F, Eley Thalia C, Lewis Cathryn M, Hamilton Steven P, Martin Nicholas G, Boomsma Dorret I, Lehto Kelli, Wray Naomi R, Breen Gerome, Penninx Brenda W J H, Milaneschi Yuri, Marshall Sally, Thomson Pippa A, Lu Yi
Аннотация
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 r g = 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.