A genome-wide association study of > 460,000 individuals of European ancestry has identified 27 genetic loci separating 2 biologically distinct subtypes of major depressive disorder (MDD) defined by opposing atypical energy-related symptoms (AERS).¹
Current diagnostic criteria count hypersomnia and insomnia, or weight gain and weight loss, as equally valid paths to an MDD diagnosis, despite opposite underlying biology. Investigators from the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, based at Karolinska Institutet, built on earlier heritability work identifying this symptom grouping as a genetically distinct target.2 The new analysis expands the approach to 3 subtypes across nearly half a million individuals.1
"[Our] lab, led by Dr. Yi Lu, works on depression subtypes, trying to look specifically at how we can group patients with MDD into subgroupings,” said Arvid Harder, of Karolinska Institutet, Stockholm, Sweden. “[This] might give us more of an idea [on] whether they respond to certain medications or whether they're caused by different things.”
AERS Subtype Definitions and GWAS Architecture
The investigators defined 3 subgroups among individuals meeting criteria for MDD:
AERS+, characterized by hypersomnia with increased appetite or weight gain (n = 47,858);
AERS−, characterized by insomnia with decreased appetite or weight loss (n = 156,624); and
Uncategorized group with mixed presentations (n = 215,828).
Across the 3 subtypes, the analysis identified 27 genome-wide significant loci: 4 for AERS+, 10 for AERS−, and 13 for Uncategorized.1 No prior MDD genetics study had reported several of these loci.
AERS+ showed greater SNP-based heritability, at 10.9%, compared with 7.9% for AERS− and 8.6% for Uncategorized. Polygenicity followed the opposite pattern: AERS+ variants accounted for 1.7% of SNPs studied, versus 2.9% for AERS− and 5.3% for Uncategorized. The study found larger effect sizes with AERS+-associated loci.1
Genetic Correlations and Metabolic Risk in MDD Subtypes
AERS+ and AERS− shared a moderate genetic correlation (rg = 0.64; SE = 0.04), indicating overlapping but partially distinct genetic architecture rather than fully separate disorders.1 Metabolic traits emerged as the primary axis of differentiation: AERS+ correlated positively with body mass index (BMI), waist circumference, metabolic syndrome, type 2 diabetes, and blood glucose, while AERS− correlated weakly in the opposite direction. Investigators note the immunometabolic profile in AERS+ resembles preclinical metabolic syndrome, while AERS− appears biologically more protective on standard metabolic markers.
AERS+ also showed a negative correlation with HDL cholesterol and a positive correlation with C-reactive protein, alongside links to ADHD, hypertension, and coronary heart disease.1 AERS− carried a genetic correlation with anorexia nervosa and had a possible shared mechanism with schizophrenia risk.
"Right now, it's hard for clinicians to make definitive changes, because the [goal] of subtyping is tailoring treatment to different subtypes," Harder said. “We're not quite there yet.”
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. Accessed August 10, 2026. doi:10.64898/2026.07.02.26357101
Mitchell BL, Monistrol-Mula A, Thomas JT, Byrne EM. The Role of Genetic Data in Dissecting Depression Heterogeneity. Biol Psychiatry. 2026;99(12):1100-1109. doi:10.1016/j.biopsych.2025.10.029
