Atypical energy-related symptoms define biologically distinct subtypes of major depressive disorder
Harder, A.; Wang, R.; Bergstedt, J.; Huider, F.; Kurvits, S.; Thorp, J.; Gong, T.; Assary, E.; Thijssen, A. B.; Merola, G. P.; Goula, A. A.; Bentwood, S.; Karlsson, R.; Pasman, J. A.; Fabbri, C.; Hickie, I. B.; Peyrot, W. J.; Levinson, D. F.; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, ; Potash, J. B.; Shi, J.; Medland, S. E.; Mitchell, B. L.; Kwong, A. S. F.; Eley, T. C.; Lewis, C. M.; Hamilton, S. P.; Martin, N. G.; Boomsma, D. I.; Lehto, K.; Wray, N. R.; Breen, G.; Penninx, B. W. J. H.; Milaneschi, Y.; Marshall, S.; Thomson, P. A.; Lu, Y.
Show abstract
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 (N_eff = 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.
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