A genome-wide association meta-analysis with > 460,000 participants has identified 2 genetically distinct subtypes of major depressive disorder (MDD): AERS+ (hypersomnia with increased appetite and weight gain) and AERS− (insomnia with appetite and weight loss). These subtypes diverge in heritability, polygenicity, and metabolic genetic correlations.¹
Current MDD diagnostic criteria treat opposite-direction neurovegetative symptoms, weight gain versus weight loss, and hypersomnia versus insomnia as clinically interchangeable.¹ The investigators, working within the Psychiatric Genomics Consortium's MDD working group, stratified individuals meeting MDD criteria into AERS+, AERS−, and an uncategorized group before running subtype-specific genome-wide association analyses.¹ The approach builds on the research team's earlier coverage of the AERS framework's genetic architecture.²
"We know if you're at a higher BMI, your subsequent risk of depression increases, and vice versa," said Arvid Harder, lead study author. "We are unable to make any claims about the [causal architecture]. We just show they co-occur together, but we don't know exactly [how]."
AERS+ and AERS− Subtypes Show Distinct GWAS Architecture
The meta-analysis pooled data across cohorts to reach effective sample sizes of 47,858 for AERS+, 156,624 for AERS−, and 215,828 for the uncategorized group. Across the 3 groups, the investigators identified 27 genome-wide significant loci, including 4 for AERS+, 10 for AERS−, and 13 for the uncategorized group.¹
AERS+ showed a greater SNP-based heritability (10.9%) than AERS− (7.9%) or the uncategorized group (8.6%), despite its smaller sample size. AERS+ also showed lower polygenicity, with associated variants covering an estimated 1.7% of SNPs compared with 2.9% for AERS− and 5.3% for the uncategorized group, and larger effect sizes at its associated loci. AERS+ and AERS− were moderately genetically correlated (rg = 0.64; SE = 0.04), indicating overlapping but distinguishable genetic architecture between the 2 symptom-direction subtypes.¹
Metabolic Genetic Correlations Distinguish MDD Subtypes
Metabolic traits emerged as the primary axis separating the subtypes. AERS+ correlated positively with BMI, metabolic syndrome, and related metabolic traits, while AERS− correlated weakly in the opposite direction.¹
Harder said the pattern may reflect how genetic studies of clinical traits also capture biomarkers shaped by a person's current body weight rather than depression biology alone. AERS−, marked by weight loss during a depressive episode, showed a genetic link to anorexia nervosa alongside more favorable metabolic markers, a pattern Harder attributed partly to weight-related masking of the underlying depression signal.
The findings identify metabolic biology as a central axis differentiating MDD subtypes beyond mood symptoms alone. Harder said continuous assessment of symptom directionality, rather than a single unified depression score, could eventually guide treatment selection if subgroup-specific treatment response is confirmed in future trials.
“It's very nice to kind of have this dialogue between clinicians and researchers on how we should continuously develop these instruments and which questions we ask,” Harder said.
References
Harder A, Wang R, Bergstedt J, et al. Atypical energy-related symptoms define biologically distinct subtypes of major depressive disorder. medRxiv. Preprint posted July 2, 2026. doi:10.64898/2026.07.02.26357101
